Ultrasound in Med. & Biol., Vol. -, No. -, pp. 1–13, 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.2015.05.018

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Original Contribution ACOUSTIC RADIATION FORCE IMPULSE ELASTOGRAPHY IN THE DIAGNOSIS OF THYROID NODULES: USEFUL OR NOT USEFUL? YI-FENG ZHANG,*z HUI-XIONG XU,*yz JUN-MEI XU,*z CHANG LIU,*z LE-HANG GUO,*z LIN-NA LIU,*z JING ZHANG,*z XIAO-HONG XU,y SHEN QU,zx and MINGZHAO XINGz{ * Department of Medical Ultrasound, Shanghai 10th People’s Hospital, Tongji University School of Medicine, Shanghai, China; y Department of Ultrasound, Guangdong Medical College Affiliated Hospital, Zhanjiang, China; z Thyroid Institute, Tongji University School of Medicine, Shanghai, China; x Department of Endocrinology and Metabolism, Shanghai 10th People’s Hospital, Tongji University School of Medicine, Shanghai, China; and { Department of Endocrinology, Diabetes & Metabolism, Johns Hopkins University School of Medicine, Baltimore, MD, USA (Received 16 August 2014; revised 21 May 2015; in final form 22 May 2015)

Abstract—The goal of this study is to evaluate the diagnostic performance of acoustic radiation force impulse (ARFI) elastography for differentiating benign from malignant thyroid nodules. One hundred and seventy-four pathologically proven thyroid nodules (139 benign, 35 malignant) in 154 patients (mean age: 49.2 ± 12.1 y; range: 16–72 y) were included in this study. Conventional ultrasound (US) and ARFI elastography using virtual touch tissue imaging (VTI) and virtual touch tissue quantification (VTQ) were performed to examine the thyroid nodules. Two blinded readers with different amounts of experience independently scored the likelihood of malignancy on the basis of a five-point scale in three different image-reading sets. The diagnostic performances among different image-reading sets and between the two readers were compared. The diagnostic specificity of both readers improved significantly after reading the VTI images or both VTI and VTQ images (all p , 0.05). After review of the results of both VTI and VTQ, the numbers of correctly diagnosed nodules increased in nodules ,1.0 cm for both readers and in both nodular goiter and papillary thyroid carcinoma for the junior reader (p , 0.05). The nodules with definite diagnoses (i.e., confidence levels including definite benign and definite malignant cases) increased after review of VTI and VTQ images versus conventional US for the senior reader (p , 0.05). In conclusion, adding ARFI elastography improves the specificity in diagnosing malignant thyroid nodules compared with conventional US on its own. ARFI elastography particularly facilitates the specific diagnosis for thyroid nodules smaller than 1.0 cm. ARFI elastography is also able to increase the diagnostic confidence of the readers. (Email: [email protected]) Ó 2015 World Federation for Ultrasound in Medicine & Biology. Key Words: Acoustic radiation force impulse, Thyroid nodule, Ultrasound, Elastography.

and positive predictive value (PPV) of US to predict whether a thyroid nodule is benign or malignant were 17.4%–87.1%, 38.9%–95.0%, 9.3%–70.7% and 38.9%– 97.8%, respectively (Frates et al. 2005). To further improve the diagnostic capability, US elastography has been introduced as a supplementary diagnostic method in the evaluation of thyroid nodules. US elastography is able to reflect the tissue stiffness qualitatively or semiquantitatively, and malignant lesions are often characterized by greater stiffness than benign and normal tissue (Asteria et al. 2008). The sensitivity, specificity, PPV and NPV for thyroid elastography in the diagnosis of malignant thyroid nodules were reported to be 86%–97%, 85%–100%, 95%–100% and 98%–100%, respectively (Bojunga et al. 2010; Friedrich-Rust et al. 2007; Gietka-Czernel et al. 2010; Lupsor et al. 2009; Rago et al. 2007; Sporea et al. 2011), which indicates that

INTRODUCTION Thyroid nodules are a common clinical problem, and the incidence of thyroid cancer has increased significantly in recent decades (Davies and Welch 2006; Wang and Wang 2015). The differential diagnosis for thyroid nodules is becoming increasingly important for clinical management. Ultrasound (US) is a useful method for the detection of thyroid nodules, but it has moderate and variable accuracy in the differential diagnosis between benign and malignant thyroid nodules. The sensitivity, specificity, negative predictive value (NPV)

Address correspondence to: Hui-Xiong Xu, Department of Medical Ultrasound, Shanghai 10th People’s Hospital, Tongji University School of Medicine, No. 301, Yanchangzhong Road, Shanghai 200072, China. E-mail: [email protected] 1

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thyroid elastography is a promising technique that can be used to improve the differential diagnosis of thyroid nodules. However, there are some opposing opinions regarding the use of elastography in thyroid nodules. A recent study indicated that the sensitivity, specificity, PPV, NPV and accuracy of real-time elastography (RTE) in differentiating between benign and malignant thyroid nodules were inferior to conventional US (Moon et al. 2012). Lippolis et al. (2011) also reported relatively low value of RTE in the differential diagnosis of thyroid lesions and that the corresponding sensitivity, specificity, PPV and NPV were 88.9%, 6%, 34% and 50%, respectively. Therefore, the role of conventional US elastography seems to be controversial. A possible explanation for these conflicting results is that the diagnostic ability of RTE may vary depending on the amount of externally applied compression as well as the individual experience of the operator (Park et al. 2009); RTE can only provide qualitative or semi-quantitative information about the tissue elasticity. Acoustic radiation force impulse (ARFI) elastography is a new technique to evaluate tissue stiffness. ARFI elastography includes virtual touch tissue imaging (VTI) and virtual touch tissue quantification (VTQ). VTI is based on longitudinal displacement of tissue under the push of short-duration acoustic pulses, while VTQ is based on the point measurement of the speed of the transverse shear waves propagating away from the pushing location. The average shear wave speed (SWS) within the point can be measured in m/s. ARFI elastography has been used in the assessment of liver fibrosis, thyroid nodules and breast nodules; for the characterization of atherosclerotic plaques; and for monitoring the results of radiofrequency ablation (Allen et al. 2011; Fahey et al. 2005; Karlas et al. 2011; Kwon et al. 2011; Tozaki et al. 2011; Zhai et al. 2008; Zhang et al. 2012). As for thyroid diseases, some studies found that ARFI elastography was able to reflect the elasticity changes of thyroid tissue in diffuse diseases (Sporea et al. 2011, 2012) and it had a relatively high value in differentiating malignant from benign lesions (Bojunga et al. 2012; Deng et al. 2014; Friedrich-Rust et al. 2012; Grazhdani et al. 2014; Gu et al. 2012; Xu et al. 2014a; Zhang et al. 2012). However, the majority of the previous studies only analyzed the imaging data of thyroid ARFI, giving the cut-off SWS value as well as the associated diagnostic value. Such a study design does not conform to clinical reality; thus, the real impact of ARFI elastography to clinical practice is questionable. In clinical reality, conventional US is generally performed first, and then ARFI, including VTI and VTQ, is carried out. In this process, the diagnostic confidence or the diagnosis for a specific disease may or may not change after ARFI; in addition, readers with different

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types and degrees of experience may obtain different results. Unfortunately, no study design regarding ARFI had simulated this diagnostic sequence and evaluated the change in diagnostic confidence and the specific diagnosis, as well as the influence of readers with different experience. In the present study, the diagnostic performance of US in differentiating benign from malignant thyroid nodules before and after ARFI elastography was compared, and the results were read by two independent, blinded readers with different experience. The aim of the present study was to assess the diagnostic capability of ARFI in diagnosing thyroid nodules under a faithfully replicated clinical diagnostic sequence. MATERIALS AND METHODS Patients This retrospective study included 174 thyroid nodules from 154 patients between April 2011 and May 2012; all the nodules were confirmed by histopathologic diagnosis with specimens obtained from surgery. Informed consent was obtained from all patients to include their data in the analysis, and the study was approved by the Ethical Committee of our university hospital. The inclusion criteria for the patients were as follows: (i) thyroid nodule $0.7 cm in diameter, as the size of the region of interest (ROI) for VTQ of ARFI is fixed at 0.6 cm 3 0.5 cm; (ii) the nodules were solid or predominantly solid (solid portion of nodule .75%) on US (Frates et al. 2005); (iii) there was enough thyroid tissue around the nodule at the same depth; and (iv) no treatment or interventional procedures had been performed on the nodule. The flowchart of the patient selection is shown in Figure 1. The patients included 45 men and 109 women. The patient age ranged from 16 to 72 y and the mean age was 49.2 6 12.1 y. The diameter of the nodules ranged from 0.7 cm to 6.0 cm (mean, 2.0 6 1.1 cm). Seventy-one patients had a single nodule and 83 had multiple nodules. For the patients with multiple nodules, nodules suspicious for malignancy or the largest solid nodule were selected for analysis. The final diagnoses of the lesions included 39 malignant and 135 benign thyroid lesions. Of the benign lesions, 128 were nodular goiter and 7 were adenoma; for malignant lesions, papillary thyroid carcinoma was diagnosed in 38 nodules and medullary thyroid carcinoma in 1 case. Conventional US All US studies were performed with the same S2000 US machine (Siemens Medical Solutions, Mountain View, CA, USA). A 9 L4-linear transducer (frequency range, 4–9 MHz) was used for the thyroid examination. The same machine and transducer were also applied to ARFI elastography examination.

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Fig. 1. The flowchart of patient selection with thyroid nodules.

The US examination was performed by experienced ultrasonologists with at least 4 y of experience in thyroid US and 2 y of experience in ARFI. The patients were placed in a supine position with dorsiflexion of the neck. The frequency, gain, focus position and depth were adjusted appropriately to ensure that the nodules displayed completely and conspicuously on the screen. In this study, conventional US examinations were all performed under tissue harmonic mode. On conventional gray-scale US, the following US features of the nodules were evaluated: echogenicity (hyper-, iso-, or hypoechogenicity, with reference to adjacent thyroid parenchyma), halo sign (presence or absence), calcification (microcalcification, hyper-echoic spots less than 2 mm, without acoustic shadowing; macrocalcification, hyperechoic spots larger than 2 mm), shape of the nodules (ovoid to round, taller than wide, or irregular) and margin of the nodules (well-defined or ill-defined). For color

Doppler US examination, the color box was adjusted to include the target lesion with some surrounding tissue (about 30% of the entire image). The transducer was gently applied to the body surface so that the small vessels in the lesion were well displayed. The color Doppler US patterns of the lesions were classified into three types: type I, absence of Doppler signals; type II, peri-nodular and absent or slight intra-nodular blood flow; or type III, marked intra-nodular and absent or slight perinodular blood flow. All the conventional US images and the following ARFI images were obtained in longitudinal planes of the nodules. ARFI elastography ARFI elastography was performed using conventional US. ARFI elastography involves targeting an anatomic region to be interrogated for elastic properties with the use of an ROI for VTQ or sampling box for

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VTI while performing real-time B-mode imaging. VTI is a gray-scale display of relative tissue stiffness in a userdefined region. This information is computed by examining the displacement of tissue elements in response to an acoustic push pulse. In VTI, the movements of the tissue along the ARFI push pulse direction are followed by speckle-tracking, in the same way as for strain elastography using manual probe palpation. In addition to displacing the tissue residing within the acoustic push pulse path, shear waves are generated after the application of the focused push pulse. These shear waves propagate perpendicular to the push pulse. Shear waves are rapidly attenuated, with an attenuation coefficient significantly higher than that of longitudinal ultrasound waves. There is a close correlation between tissue elasticity and its associated SWS. VTQ technique measures the transverse propagation of shear waves and gives the SWS value in a selected ROI. The acoustic power in VTI and VTQ is within the safety limits prescribed by the U.S. Food and Drug Administration. For VTI and VTQ, the mechanical index is ,1.7 (safety threshold is 1.9) and the intensity spatial peak temporal peak is #500 mW/cm2 (safety threshold is 720 mW/cm2). When performing ARFI, the transducer was gently applied to the body surface with light pressure on the thyroid, which is an important practical point for both VTI and VTQ examinations as even slight probe pressure can significantly increase tissue stiffness. Patients were asked to hold their breath, at which point the ARFI function was initiated. VTI was carried out first. The sampling box was adjusted to include the whole lesion and some surrounding thyroid tissue. The calculation of tissue elasticity distribution was performed and the result was represented as gray-scale image over the conventional B-mode image, in which dark indicates hard tissue and bright indicates soft tissue. The measurement was repeated until at least two clear VTI imagines were obtained. The VTI images were classified into one of six scores according to Xu’s VTI scoring system (Xu et al. 2014a; Zhang et al. 2014a) by one ultrasonologist onsite: (i) Score 1: the nodule is displayed as predominantly bright; (ii) Score 2: the nodule is displayed as predominantly bright with a few dark portions; (iii) Score 3: the nodule is displayed as equally dark and bright; (iv) Score 4: the nodule is displayed as predominantly dark with a few bright spots; (v) Score 5: the nodule is displayed as almost completely dark; and (vi) Score 6: the nodule is displayed as completely dark without bright spots. VTQ was performed after VTI. The criteria for ROI selection were as follows: (i) ROI was placed on the solid portion of the nodule, always at the peripheral part of the nodule; (ii) calcified and liquefaction necrosis portions of the nodule were avoided; (iii) the adjacent thyroid tissue was not included in ROI; and (iv) the depth of the ROI

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ranged from 0.5 to 2.5 cm. The size and the location of the ROI did not change to sample different parts of the thyroid nodule to avoid inconsistency of the SWS measurement. When VTQ of ARFI was initiated, the SWSs of the tissue in the ROI were calculated and displayed onscreen. Seven consecutive measurements for each nodule were performed without movement of the transducer. The highest and lowest values were eliminated, and the mean of the remaining five measurements was calculated and used for the analysis. The range for the SWS was 0–8.41 m/s. Values displayed as ‘‘x.xxm/s’’ indicated failed shear wave estimates and were not included in the calculation for mean SWS. All the conventional US images, VTI images and VTQ results were stored digitally in the hard disk of the US machine and were transferred to a personal computer for subsequent review. The data acquisition procedure took approximately 5–10 min for each patient. It added no additional cost and caused no inconvenience to the patients. Image reading procedures The images were retrospectively analyzed by two independent readers who had at least 15 y (reader 1, senior reader) and 3 y (reader 2, junior reader) of experience in thyroid US and at least 3 y (reader 1, senior reader) and 2 y (reader 2, junior reader) of experience in thyroid elastography examination. They were not involved in the scanning and were blinded to patient identification, clinically relevant information, histopathology results and other imaging results. The individual cases were presented in a randomized order so that the benign and malignant cases were not grouped by diagnosis, and any identifying information (i.e., the sequence number, name, sex and age of each patient) was concealed. The reading procedures were carried out in three steps. In step 1, the two readers were asked to review the conventional US images of each nodule, including color Doppler US images, and were then assigned a confidence rating score for each nodule on the basis of a five-point scale (1, definitely benign; 2, probably benign; 3, indeterminate; 4, probably malignant; 5, definitely malignant). If it was possible, further the readers were asked to make a specific diagnosis for the lesion. For example, a lesion could be diagnosed as ‘‘thyroid papillary carcinoma’’ instead of ‘‘malignant thyroid nodule’’ or as ‘‘nodular goiter’’ instead of ‘‘benign lesion.’’ In step 2, the procedure was repeated after adding VTI images for analysis. In step 3, the procedure was repeated again after adding VTQ results for analysis (i.e., including the information for conventional US, VTI and VTQ). Two interpretation sessions with a 1-wk interval were held for each reader to review the conventional US, VTI images and VTQ results (Figs. 2–5).

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Fig. 2. Images of a 65-y-old man with papillary thyroid carcinoma. (a) Conventional US showed iso-echoic, irregular margins; microcalcifications. (b) Color Doppler ultrasound showed rich intra-nodular blood flow. (c) Score 5 was assigned at VTI. (d) The SWS of the nodule was 3.26 m/s. After reading the conventional US image alone, the reader 1 classified the lesion as a high risk of malignancy score of 4 (probably malignant), and reader 2 classified the lesion as a likelihood of malignancy score of 3 (indeterminate). After reading the conventional US and VTI images, the two readers classified the lesion as a likelihood of malignant score of 5 (definitely malignant). After reading the conventional US, VTI and VTQ images, the two readers changed it to a likelihood of malignancy score of 3 (indeterminate). US 5 ultrasound; VTI 5 touch tissue imaging; SWS 5 shear wave speed; VTQ 5 virtual touch tissue quantification.

The diagnostic criteria for benign thyroid focal lesions on conventional US were absence of calcifications, cystic or nearly entirely cystic lesions, iso-echogenicity, spongiform appearance, regular margins and halo sign. The diagnostic criteria for malignant lesions were solid lesion, microcalcifications, marked hypo-echogenicity, irregular margins, absence of a halo and taller-thanwide shape (Moon et al. 2008). The diagnostic criteria on VTI were a VTI score of 1, 2 or 3 for benign nodules and a VTI score 4 or greater for malignant nodules (Xu et al. 2014a; Zhang et al. 2014a). The diagnostic criteria on VTQ were an SWS value #2.87 m/s for benign nodules and SWS value .2.87 m/s for malignant nodules (Zhang et al. 2012). The VTI strain and SWS cut-offs were derived from previous publications (Xu et al. 2014a; Zhang et al. 2012, 2014a). To

investigate whether nodule size would affect the diagnostic performance, the nodules were divided into three groups: Group 1: nodule ,1.0 cm; Group 2: nodule 1.0–2.0 cm; Group 3: nodule .2.0 cm. Statistical analysis The diagnostic confidence with respect to differentiation between benign and malignant thyroid nodules was evaluated by receiver operating characteristic curve analysis, in which the diagnostic performance was expressed as area under the receiver operating characteristic curve (AZ). The comparison of AZ derived from conventional US, adding VTI images and adding both VTI and VTQ images was evaluated by univariate Z score test. The lesions assigned a confidence grade of 3, 4 or 5 were defined as positive results (i.e., presence of malignancy),

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Fig. 3. Images of a 50-y-old man with nodular goiter. (a) Conventional US showed hypo-echogenicity, regular margins and halo sign of the nodule. (b) Color Doppler ultrasound showed peri-nodular and slight intra-nodular blood flow. (c) Score 2 was assigned at VTI. (d) The SWS of the nodule was 1.83 m/s. After reading the conventional US image alone, the two readers classified the lesion as a likelihood of malignancy score of 3 (indeterminate). After reading the conventional US and VTI images, the two readers classified the lesion as a likelihood of benign score of 2 (probably benign). After reading the conventional US, VTI and VTQ images, the two readers changed it to a likelihood of benign score of 1 (definitely benign). US 5 ultrasound; VTI 5 touch tissue imaging; SWS 5 shear wave speed; VTQ 5 virtual touch tissue quantification.

and those assigned a confidence grade of 2 or less were defined as negative results (i.e., absence of malignancy). Differences in sensitivity, specificity, accuracy and correctly characterized nodules were tested using the McNemar test; those differences in PPV and NPV were tested by c2 test or Fisher’s exact test. The comparisons between the three different groups (Group 1: nodule ,1.0 cm; Group 2: nodule 1.0–2.0 cm; Group 3: nodule .2.0 cm) were also assessed by c2 test. A p , 0.05 was considered to indicate a statistically significant difference. Inter-observer agreement in diagnostic performance with or without VTI and VTQ images was evaluated by weighted k statistics. Agreement was graded as poor (k , 0.20), moderate (k 5 0.20 to ,0.40), fair (k 5 0.40 to ,0.60), good (k 5 0.60 to ,0.80) or very good (k 5 0.80–1.00). The statistical

analyses were performed using the SPSS 17.0 software package (SPSS Inc, Chicago, IL, USA). RESULTS Basic characteristics of patients and US features of thyroid nodules The basic characteristics of the patients and the US features of the thyroid nodules are presented in Table 1. Malignant nodules were more frequently found in female patients (female/male: 30/5) than benign nodules (female/male: 79/40) (p 5 0.03). The mean maximal diameter of the malignant nodules (1.4 cm 6 0.9) (95% confidence interval [CI]: 1.20, 1.73) was significantly smaller than that of the benign nodules (2.2 cm 6 1.1) (95% CI: 2.02, 2.42) (p , 0.01). Statistically significant

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Fig. 4. Images of a 63-y-old man with adenoma. (a) Conventional US showed hypo-echogenicity, regular margins and a taller than wide–shape of the nodule. (b) Color Doppler ultrasound showed peri-nodular and slight intra-nodular blood flow. (c) Score 4 was assigned at VTI. (d) The SWS of the nodule was 1.40 m/s. After reading the conventional US image alone, the two readers classified the lesion as score of 2 (probably benign). After reading the conventional US and VTI images, the two readers classified the lesion as a likelihood of malignancy score of 3 (indeterminate). After reading the conventional US, VTI and VTQ images, the two readers downgraded it to a likelihood of benign score of 2 (probably benign). US 5 ultrasound; VTI 5 touch tissue imaging; SWS 5 shear wave speed; VTQ 5 virtual touch tissue quantification.

conventional US features for differential diagnosis of a thyroid nodule included echogenicity, calcification, shape, margin, halo sign and intra-lesional vascularity of the nodule (all p , 0.01). ARFI characteristics of thyroid nodules The ARFI characteristics, including VTI and VTQ, of the thyroid nodules are presented in Table 2. There were 10 nodules in which all the SWS measurements were shown as ‘‘x.xxm/s,’’ including two nodular goiters and eight thyroid papillary carcinomas. After discarding these nodules, the mean SWS of VTQ was 2.20 6 0.86 m/s (range: 0.61–5.17 m/s) for benign nodules and 3.74 6 1.83 m/s (range: 2.32–8.41 m/s) for malignant nodules (p , 0.001). VTI score 3 or less was found in 131 (97.0%) of 135 benign nodules and in 15 (38.5%) of 39 malignant

nodules. Conversely, VTI score 4 or higher was found in 24 (61.5%) of 39 malignant nodules and in 4 (3.0%) of 135 benign nodules (p , 0.001). Diagnostic performance before and after review of VTI and VTQ images The diagnostic performance results are summarized in Table 3. For both readers, the diagnostic performance in Az, sensitivity, PPV and NPV did not achieve significant improvement after adding the VTI images or both VTI and VTQ for analysis compared with conventional US alone (all p . 0.05), whereas the specificity increased significantly after adding the VTI images or VTI plus VTQ (both p , 0.05). In addition, the accuracy increased significantly after adding VTI plus VTQ for reader 1 (p , 0.05).

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Fig. 5. Images of a 36-y-old man with papillary thyroid carcinoma. (a) Conventional US showed hypo-echogenicity, irregular margins and microcalcifications. (b) Color Doppler ultrasound showed slight intra-nodular blood flow. (c) Score 4 was assigned at VTI. (d) The SWS of the nodule was 4.65 m/s. After reading the conventional US image alone, the two readers classified the lesion as a likelihood of malignancy score of 3 (indeterminate). After reading the conventional US and VTI images, the two readers classified the lesion as a high risk of malignancy score of 4 (probably malignant). After reading the conventional US, VTI and VTQ images, the two readers classified it as a likelihood of malignant score of 5 (definitely malignant). US 5 ultrasound; VTI 5 touch tissue imaging; SWS 5 shear wave speed; VTQ 5 virtual touch tissue quantification.

For the comparison between the two readers, there was no difference in diagnostic performance between the two readers after reading conventional US images alone. However, the specificity and accuracy for reader 1 (i.e., senior reader) were significantly better than that for reader 2 (i.e., junior reader) after adding the VTI images for analysis (both p , 0.05). Specific diagnosis for thyroid nodules In comparison with conventional US alone, after addition of the VTI and VTQ images, the numbers of correctly diagnosed nodules increased significantly in both nodular goiter (from 77.3% to 88.3%) and papillary thyroid carcinoma (from 47.4% to 71.1%) for the junior reader (both p , 0.05), whereas only nodular goiter diagnosis improved for the senior reader (from 73.4% to 85.2%; p , 0.05).

With regard to the influence of nodule size to diagnostic performance of ARFI, the numbers of correctly diagnosed nodules increased significantly in nodules sized ,1.0 cm for both readers after addition of the VTI and VTQ images. Significant increase was also found in all nodules for reader 1 after the addition of the VTI and VTQ images. However, no significant increase was found both in the 1.0–2.0 cm and .2.0 cm nodules after adding the images of VTI or VTI plus VTQ for analysis (Table 4). Confidence level and inter-observer agreement For the 174 thyroid nodules, the number of definitely benign nodules increased significantly for reader 1 (senior reader) after addition of the VTI and VTQ images versus conventional US only (from 71 to 93; p , 0.05). The number of definitely malignant nodules also

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Table 1. The basic characteristics of the patients and the US features of the thyroid nodules

Patient (n 5 154) Gender (female/male) Age (y)y Single nodule/multiple nodule Nodule (n 5 174) Size (cm)y Location Left Right Isthmus Echogenicity Hyper-echoic Iso-echoic Hypo-echoic Mixed Calcification None Microcalcification Macrocalcification Shape Ovoid to round Taller than wide Irregular Margin Well-defined Ill-defined Halo sign Present Absent Vascularity Type I Type II Type III

Benign

Malignant

119 79/40 49.5 6 12.4 (16–70) 51/68 135 2.2 6 1.1 (0.7–6.0)

35 30/5 48.1 6 11.4 (27–72) 20/15 39 1.4 6 0.9 (0.7–4.0)

70 (51.9%) 62 (45.9%) 3 (2.2%)

18 (46.2%) 19 (48.7%) 2 (5.1%)

1 (0.7%) 44 (32.6%) 69 (51.1%) 21 (15.6%)

1 (2.6%) 1 (2.6%) 37 (94.8%) 0

118 (87.4%) 7 (5.2%) 10 (7.4%)

17 (43.6%) 16 (41.0%) 6 (15.4%)

125 (92.6%) 2 (1.5%) 8 (5.9%)

20 (51.3%) 11 (28.2%) 8 (20.5%)

108 (80.0%) 27 (20.0%)

20 (51.3%) 19 (48.7%)

79 (58.5%) 56 (41.5%)

2 (5.1%) 37 (94.9%)

59 (43.7%) 67 (49.6%) 9 (6.7%)

21 (53.8%) 8 (20.5%) 10 (25.7%)

p* 0.03 0.37 0.14 ,0.001 0.57

,0.001

,0.001

,0.001

,0.001 ,0.001 ,0.001

* p values indicate comparison between benign and malignant nodules. y Data in parenthesis indicate ranges, otherwise percentages.

increased significantly after review of VTI images (from 0 to 7; p , 0.01) and after review of VTI and VTQ images (from 0 to 18; p , 0.01) versus conventional US only. The number of indeterminate nodules decreased significantly after review of VTI images (from 43 to 28) and after review of both VTI and VTQ images (from 43 to 12) versus conventional US only (p , 0.05) for reader 1. As for reader 2, the number of indeterminate nodules also decreased significantly after review of both VTI and VTQ images (from 32 to 19) versus conventional US only (p , 0.05). The inter-observer agreement of the two readers increased from fair (k 5 0.49 6 0.09 (standard error); 95% CI: 0.31–0.66) to good (k 5 0.64 6 0.08; 95% CI: 0.48–0.80) after review of the VTI images, but decreased to fair (k 5 0.54 6 0.08; 95% CI: 0.38–0.70) again after review of both the VTI and VTQ images. DISCUSSION In order to distinguish benign from malignant thyroid nodules and reduce unnecessary fine-needle aspiration in benign thyroid nodules, elastography has been

introduced as a supplement to conventional US. Some previous studies have indicated that RTE can be used with a high sensitivity and a good specificity to differentiate malignant from benign thyroid nodules, whereas other studies have shown that the value of RTE in discriminating malignant from benign lesions was unsatisfactory and the reproducibility of RTE was relatively low (Heged€us 2010; Lippolis et al. 2011; Moon et al. 2012). Moon et al. (2012) found that the sensitivity, NPV and odds ratio for gray-scale US were 91.7%, 94.7% and 22.1%, respectively, higher than the 15.7%– 65.4% sensitivity, 71.7%–79.1% NPVand 2.6–3.7 odd ratios found for RTE in their study with 703 solid thyroid nodules. Therefore, there is strong need for quantitative analytical tools rather than a subjective colorimetric scale for the assessment of nodule stiffness (Lippolis et al. 2011). ARFI is a new technology for evaluating tissue stiffness quantitatively and qualitatively. ARFI includes VTI and VTQ, in which VTQ gives an objective numerical evaluation of the tissue stiffness by calculating the SWS and VTI represents a qualitative response to acoustic pulse that displays as a gray-scale map. Recent studies

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Table 2. The ARFI characteristics of the thyroid nodules Benign (n 5 135)

VTI Score Score 1 Score 2 Score 3 Score 4 Score 5 Score 6 VTQ (m/s) Meany Range

Malignant (n 5 39)

,1.0 cm

1.0–2.0 cm

.2.0 cm

Total

,1.0 cm

1.0–2.0 cm

.2.0 cm

Total

3 (2.2%) 4 (3.0%) 7 (5.3%) 1 (0.7%) 0 0

28 (20.7%) 12 (8.9%) 6 (4.4%) 1 (0.7%) 1 (0.7%) 0

51 (37.8%) 17 (12.6%) 3 (2.2%) 1 (0.7%) 0 0

82 (60.7%) 33 (24.5%) 16 (11.9%) 3 (2.2%) 1 (0.7%) 0

0 1 (2.6%) 7 (17.9%) 6 (15.4%) 0 1 (2.6%)

0 1 (2.6%) 4 (10.2%) 8 (20.5%) 3 (7.7%) 1 (2.6%)

0 1 (2.6%) 1 (2.6%) 4 (10.3%) 1 (2.6%) 0

0 3 (7.7%) 12 (30.7%) 18 (46.2%) 4 (10.2%) 2 (5.2%)

2.74 6 0.83 (2.39,3.08) 1.16–4.12

2.23 6 0.80 (2.01,2.45) 0.92–4.02

2.03 6 0.86 (1.82,2.24) 0.61–5.17

2.20 6 0.86 (2.06,2.35) 0.61–5.17

3.42 61.61 (2.67,4.30) 2.43–7.97

3.71 6 1.83 (2.94,4,59) 2.32–8.41

5.65 6 2.43 (3.81,7.58) 2.67–7.59

3.74 6 1.83 (3.18,4.37) 2.32–8.41

p* ,0.001

,0.001

VTI 5 virtual touch tissue imaging; VTQ 5 virtual touch tissue quantification. VTI images score system (Dark indicates hard tissue and bright indicates soft tissue): Score 1: the nodule is displayed as predominantly bright. Score 2: the nodule is displayed as predominantly bright with a few dark portions. Score 3: the nodule is displayed as equally dark and bright. Score 4: the nodule is displayed as predominantly dark with a few bright spots. Score 5: the nodule is displayed as almost completely dark. Score 6: the nodule is displayed as completely dark without bright spots. * p values indicate the comparison between total benign and total malignant nodules. y Data in parenthesis indicates 95% confidence intervals, otherwise percentages.

indicated that ARFI was valuable in discriminating malignant from benign thyroid lesions. The sensitivity, specificity, accuracy, PPVand NPV for ARFI were 57%–86%, 82%–93%, 79%–82%, 59%–95% and 38%–91%, respecTable 3. Diagnostic performance in differentiating malignant from benign thyroid nodules before and after review of VTI and VTQ images Image reading sets Performance parameters AUC Reader 1z Reader 2z Sensitivity, % Reader 1x Reader 2x Specificity, % Reader 1x Reader 2x PPV, % Reader 1x Reader 2x NPV, % Reader 1x Reader 2x Accuracy, % Reader 1x Reader 2x

US

US1VTI

US1VTI1VTQ

0.87 (0.81–0.92) 0.89 (0.83–0.95) 0.83 (0.76–0.90) 0.81 (0.73–0.88)

0.86 (0.79–0.94) 0.84 (0.74–0.91)

97.4 (38/39) 87.2 (34/39)

82.1 (32/39) 84.6 (33/39)

92.3 (36/39) 87.2 (34/39) ,y

75.6 (102/135) 78.5 (106/135)

85.2 (115/135)* 74.1 (100/135)

90.4 (122/135)* 83.0 (112/135)

53.5 (38/71) 54.0 (34/63)

64.2 (36/56) 49.3 (34/69)

71.1 (32/45) 58.9 (33/56)

99.0 (102/103) 95.5 (106/111)

97.4 (115/118) 95.2 (100/105)

94.6 (122/129) 94.9 (112/118)

80.4 (140/174) 80.4 (140/174)

86.8 (151/174)y 77.0 (134/174)

88.5 (154/174)* 83.3 (145/174)

US 5 ultrasound; VTI 5 virtual touch tissue imaging; VTQ 5 virtual touch tissue quantification. * p , 0.05, in comparison with US only. y p , 0.05, in comparison with Reader 2. z Data in parenthesis indicate 95% confidence interval. x Data are percentages (with numbers used to calculate percentages in parentheses).

tively (Bojunga et al. 2012; Zhang et al. 2012). ARFI also achieved high inter-observer and intra-observer reproducibility (Zhang et al. 2012). However, to date, the diagnostic value of ARFI had not been compared with conventional US using a blinded reader analysis. The blinded analysis is believed to be useful to assess the real effect of ARFI in clinical practice and to solve the controversy over elastography. Furthermore, the diagnostic value of ARFI elastography should be evaluated under a faithfully replicated clinical diagnostic sequence, as shown in the present study where elastography was Table 4. Number of nodules correctly characterized in 174 thyroid nodules according to size before and after review of only VTI as well as VTI and VTQ No. of nodules correctly characterized ,1.0 cm (n 5 30) Reader 1 US US1VTI US1VTI1 VTQ Reader 2 US US1VTI US1VTI1 VTQ

1.0–2.0 cm (n 5 65)

.2.0 cm (n 5 79)

Total (n 5 174)

11 (36.7%) 42 (64.6%)* 65 (82.3%)*,y 118 (67.8%) 14 (46.7%) 49 (75.4%)* 66 (83.5%)* 129 (74.1%) 18 (60.0%)z 52 (80.0%)* 68 (86.1%)* 138 (79.3%)z 13 (43.3%) 42 (64.6%) 66 (83.5%)*,y 121 (69.5%) 12 (40.0%) 45 (69.2%)* 69 (87.3%)* 126 (72.4%) 17 (56.7%)z 51 (78.5%)* 69 (87.3%)* 137 (78.7%)

US 5 ultrasound; VTI 5 virtual touch tissue imaging; VTQ 5 virtual touch tissue quantification. * In comparison with size ,1.0 cm, p , 0.05. y In comparison with size 1.0–2.0 cm, p , 0.05. z In comparison with reading US alone, p , 0.05.

Elastography in thyroid nodule diagnosis d Y.-F. ZHANG et al.

used as an additional feature, which was different from the study of Moon et al. (2012) wherein B-mode and RTE were contrasted rather than using the elastography as an extension to B-mode US. In the present study, the Az, sensitivity, PPV and NPV did not improve significantly after adding ARFI elastography for analysis in comparison with US alone. On the other hand, it was found that the specificity increased significantly after reading the images of VTI or VTI plus VTQ for both readers, and the accuracy increased significantly after adding VTI plus VTQ in one of the readers. The result was consistent with another prospective study of approximately 1000 patients with breast masses using a different quantitative 2-D shear wave elastography (SSI, SuperSonic Imagine, Aix-enProvence, France). In that study, only the specificity increased from 61.1% for conventional US to 78.5% for 2-D shear wave elastography, whereas the sensitivity did not improve significantly (Berg et al. 2012). Although the result was somewhat disappointing, it was reasonable. Due to the high resolution of current US technology, it is easy to detect even tiny thyroid nodules and to depict the suspicious US features, therefore the sensitivity is always near 90% (87%–97% in the present study). It is hard to improve the sensitivity further, as US seldom misses thyroid malignancy based on the imaging features. It is more clinically relevant to rule out thyroid malignancy, so that interventional procedures such as fine needle aspiration or unnecessary surgery can be avoided. The improved specificity for ARFI falls within this scope, in that it is a more reliable tool to rule out thyroid malignancy. After reviewing the VTI images, the specificity and accuracy for reader 1 (the senior reader) were significantly higher than those for reader 2 (the junior reader); however, the specificity and accuracy for reader 1 were not better than reader 2 when the conventional US images were read alone. These findings indicated that more experience was necessary when ARFI was used to make differential diagnosis for thyroid nodules. Although, in general, ARFI showed equivalent performance in the differentiation of malignant from benign thyroid nodules compared with conventional US, we still found some usefulness of ARFI in the diagnosis of thyroid nodules. The study showed that the numbers of definitely benign and malignant nodules both significantly increased after review of VTI and VTQ images for the senior reader. The indeterminate nodules decreased significantly after review of both VTI and VTQ images versus conventional US alone for both readers. These results indicated that ARFI could improve the diagnostic confidence of readers. Moon et al. (2008) found that for thyroid nodules with a diameter of 1 cm or less, the sensitivity of microcalcifications, which is one of the suspicious gray-scale

11

US features, was lower than that in larger nodules. Mazzaferri and Sipos (2008) also found that RTE had high false-positive rates in nodules 5 mm or smaller. Previous studies indicated that the diagnostic value of VTQ was associated with the nodule size, with relatively high value for nodules .2.0 cm and inferior value for those #1.0 cm (Zhang et al. 2012). Guidelines do not recommend US-guided biopsy in nodules 1 cm or smaller, unless there are suspicious US findings or high-risk histories. Therefore, the diagnosis of thyroid nodules #1.0 cm is relatively difficult. In the present study, the numbers of correctly diagnosed nodules increased significantly in nodules #1.0 cm for both readers after review of VTI and VTQ images in comparison with conventional US alone. A significant increase of correctly diagnosed nodules was also found in all the nodules as a whole for reader 1 after review of VTI and VTQ images. These findings indicated that ARFI might be a new, reliable supplemental method for the diagnosis of thyroid nodules #1.0 cm. The ability of specific diagnosis for ARFI in nodular goiter and papillary thyroid carcinoma was also evaluated. Nodular goiter is the most prevalent benign thyroid nodule, and papillary thyroid carcinoma is the most common thyroid carcinoma, the incidence of which increased from 2.7 to 7.7 per 100,000 in the United States, a 2.9-fold increase from 1973 to 2002 (Davies and Welch 2006). To make correct specific diagnosis of thyroid nodules, we need to evaluate more than one gray-scale US feature of the lesion, including the echogenicity, shape, margin, calcifications, etc. If the gray-scale US features are not sufficient to make a specific diagnosis, some other diagnostic methods are needed. In the present study, the numbers of correctly diagnosed nodules increased significantly in both nodular goiter and papillary thyroid carcinoma for the junior reader; however, an increase in correct diagnoses only occurred in nodular goiter for the senior reader. ARFI could provide additional elastic information of the thyroid nodule. Therefore, it might be helpful for the inexperienced junior reader to make correct specific diagnosis for thyroid nodules, particularly when they are not sure about the diagnosis for papillary thyroid carcinoma. The present study had some limitations: First, only 174 nodules were included in this retrospective study, which might be relatively small for sensitivity comparison and the associated statistical power was only 0.66; thus, larger prospective studies are needed to confirm the role of this new technique in the diagnosis of thyroid lesions. Second, examples of a greater variety of thyroid diseases are necessary to evaluate the performance of ARFI in the diagnosis of thyroid nodules; most of the malignant nodules were papillary thyroid carcinomas in this series and only one medullary thyroid carcinoma was found. For benign nodules, only seven adenomas

12

Ultrasound in Medicine and Biology

were found in this series. Third, to ensure the accuracy of the final results, 380 cases without histology results were excluded, which might lead to a selection bias. As a result of this, the population might not reflect a normal distribution of disease. Fourthly, ARFI has some technical limitations. The elasticity features may be different in different parts of the nodule; the VTQ can only reveal the local stiffness of the nodule, instead of the entire lesion. For a thyroid nodule close to the carotid artery and trachea, the pulsation of the carotid artery and breathing might affect the VTQ measurement. Invalid measurement results such as x.xxm/s were occasionally encountered, which causes confusion in evaluation of the stiffness of the tissue. Finally, two different elastography techniques were used, strain (i.e., VTI) and shear wave (i.e., VTQ), and their diagnostic ability was not compared. However, in previous studies, VTI seemed to have a better diagnostic performance in comparison with VTQ (Xu et al., 2014b; Zhang et al., 2014b). In conclusion, ARFI is useful to increase the diagnostic specificity and to rule out the possibility of thyroid malignancy. ARFI is also valuable to increase the diagnostic confidence of investigators, especially for indeterminate lesions. ARFI can increase the specific diagnosis of thyroid nodules, especially in nodules ,1.0 cm. It should also be noted that experience is needed in interpreting ARFI images, suggesting that a learning curve is present for ARFI analysis. Acknowledgments—This work was supported in part by Grant SHDC12014229 from Shanghai Hospital Development Center, Grant 14441900900 from Science and Technology Commission of Shanghai Municipality, Grant 20144 Y0148 from Shanghai Municipal Commission of Health and Family Planning, and Grants 81401417 and 81472579 from the National Natural Science Foundation of China.

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