Med Oncol (2015) 32:50 DOI 10.1007/s12032-015-0502-5
ORIGINAL PAPER
Acoustic radiation force impulse elastography for differentiation of benign and malignant thyroid nodules with concurrent Hashimoto’s thyroiditis Bo-Ji Liu • Hui-Xiong Xu • Yi-Feng Zhang • Jun-Mei Xu • Dan-Dan Li • Xiao-Wan Bo • Xiao-Long Li • Le-Hang Guo Xiao-Hong Xu • Shen Qu
•
Received: 10 January 2015 / Accepted: 23 January 2015 Ó Springer Science+Business Media New York 2015
Abstract The purpose of the study was to explore the diagnostic performance of acoustic radiation force impulse (ARFI) elastography in differential diagnosis between benign and malignant thyroid nodules in patients with coexistent Hashimoto’s thyroiditis (HT). A total of 141 pathological proven nodules in 141 HT patients (7 males and 134 females, mean age 50.1 years, range 23–75 years) received conventional ultrasound (US), elasticity imaging (EI) and ARFI elastography, including virtual touch tissue imaging (VTI) and virtual touch tissue quantification (VTQ), before surgery. Shear wave velocity (SWV) and SWV ratio were measured for each nodule on VTQ. The US, EI and ARFI elastography features were compared between benign and malignant nodules in HT patients. Receiver operating characteristic curve (ROC) analyses and area under curve (AUC) were performed to assess the
diagnostic performance. Pathologically, 70 nodules were benign and 71 nodules were malignant. Significant differences were found between benign and malignant nodules in HT patients for EI (EI score) and ARFI (VTI grade and SWV) (all P value \0.05). The AUCs for EI, VTI, SWV and SWV ratio were 0.68 [95 % confidence interval (CI): 0.59–0.77], 0.90 (95 % CI: 0.84–0.95), 0.77 (95 %CI: 0.70–0.85) and 0.74 (95 %CI: 0.66–0.82), respectively. The cut-off points were EI score C3, VTI grade C4, SWV C2.58 m/s and SWV ratio C1.03, respectively. In conclusion, ARFI elastography is useful for differentiation between benign and malignant thyroid nodules in HT patients. The diagnostic performance of ARFI elastography is better than EI.
B.-J. Liu H.-X. Xu (&) Y.-F. Zhang J.-M. Xu D.-D. Li X.-W. Bo X.-L. Li L.-H. Guo Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China e-mail: [email protected]
Introduction
B.-J. Liu H.-X. Xu Y.-F. Zhang J.-M. Xu D.-D. Li X.-W. Bo X.-L. Li L.-H. Guo S. Qu Thyroid Institute, Tongji University School of Medicine, Shanghai 200072, China H.-X. Xu X.-H. Xu Department of Ultrasound, Guangdong Medical College Affiliated Hospital, Zhanjiang 524001, China S. Qu Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
Keywords Acoustic radiation force impulse Hashimoto’s thyroiditis Elastography Thyroid nodules
Hashimoto’s thyroiditis (HT), with an incidence of about 1 case per 1,000 persons per year [1], is a chronic autoimmune inflammation disease of the thyroid gland and now is generally considered the most common cause of hypothyroidism [2, 3]. The diagnosis of HT is usually established by the positive test for serum thyroglobulin antibody (TgAb) and/or thyroid peroxidase (TPOAb) antibody, and hypoechoic appearance for thyroid in ultrasound scan [4]. Thyroid nodules are common clinically, and the incidence is up to 50 % on ultrasound (US) examination [5]. In HT patients, some of them are true tumorous or hyperplastic nodules, while the others can be pseudo-nodules (Hashimoto nodules) when the dense fibrosis distorts the thyroid architecture and imparts to gland a lobular
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appearance in fibrous variant form of HT [6]. The clinical importance of thyroid nodules is the early detection of thyroid cancer, which has a 5 % incidence in overall thyroid nodules [7]. A higher prevalence of thyroid cancer was found in HT patients than in overall population (29.4 vs. 19.4 %), and coexisting HT for thyroid nodules increased the risk of papillary thyroid carcinoma (PTC; odds ratio value: 2.96) [8–11]. On conventional US, the echogenicity of the thyroid parenchyma in HT is usually heterogeneous since thyroid follicles are destroyed and replaced by small lymphocytes. Hypoechogenicity is considered to be one of the suspicious malignant features in thyroid nodules [12]; however, hypoechogenic appearance is common in HT patients and is always diffusely distributed in the gland. Therefore, it is difficult to diagnose malignant nodules from all nodules using conventional US in patients with coexistent HT. As a consequence of this, not few HT patients with nodules are referred to a diagnostic surgery when the fine-needle aspiration cytology (FNAC) results are indeterminate and often undergo thyroidectomy to find the pathological outcome is benign. Conventional US is the most commonly used imaging modality for thyroid diseases, the sensitivity of which in diagnosing malignant thyroid nodules ranged from 38.8 to 90.9 % in non-HT patients [12–17], while it ranged from 17.5 to 87.5 % in HT patients [18, 19]. Conventional strain elastography (SE) is a useful tool in differentiating malignant from benign thyroid nodules by enabling measurement of tissue deformation in response to compression and displaying tissue stiffness [20–23]. A metaanalysis about conventional SE reported a sensitivity and specificity of 92 and 90 %, respectively [24]. Acoustic radiation force impulse (ARFI) elastography is a further improvement in comparison with conventional SE that it could evaluate the tissue stiffness qualitatively and quantitatively. For ARFI elastography, transient pulses are used to generate propagating shear waves in the region of interest (ROI). The strain change under the push pulse is named as virtual touch tissue imaging (VTI), which uses an algorithm that is similar to that of conventional SE and is displayed as a gray-scale image. Quantitative evaluation of the tissue stiffness is named as virtual touch tissue quantification (VTQ) by calculating the shear wave velocity (SWV). The usefulness of ARFI elastography in diagnosis of thyroid nodules in general population has been confirmed by several studies [16, 17, 25, 26], whereas its usefulness in HT patients lacked sufficient evidences because of potential change of stiffness caused by lymphocyte infiltration, fibrosis and parenchyma atrophy [27–30]. In the present study, the diagnostic performance of ARFI elastography for identifying thyroid malignancy in a consecutive series of HT patients was evaluated.
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Materials and methods Patients The study was approved by the Ethical Committee of the university hospital, and informed consent was obtained from all patients. T total of 2,000 consecutive patients were examined by conventional US, conventional SE of elasticity imaging (EI) and ARFI elastography from January 2013 to September 2014. All the patients had thyroid nodules on conventional US, and the nodule diameter was not\5 mm. The patients were excluded when they met one of the following criteria: (1) patients had previous history of surgery (n = 136); (2) completely cystic or almost cystic ([50 %) appearance at conventional US (n = 85); (3) incomplete data for conventional US, EI or ARFI images (n = 68); (3) nodules that did not have pathologic confirmation (n = 1,049); and (4) pathologic outcome of the thyroid background was not concurrent HT (n = 521). When multiple nodules existed, the most suspicious one on US or the largest one was selected for examination. Finally, 141 nodules from 141 HT patients (7 males and 134 females, mean age 50.1 ± 11.9 years, range 23–75 years) were included. Conventional US, EI and ARFI Elastography Conventional US, EI and ARFI examinations were performed using the same S2000 US scanner (Siemens Medical Solutions, Mountain View, Calif, USA) with a 4–9 MHz linear transducer. The patients were positioned in supine position with dorsal flexion of the head. B-mode US and color Doppler US were performed, and the maximal diameter of the nodule was measured. EI was performed following conventional US by the same investigator. The transducer was placed on the body surface, and a light pressure was applied. Continuous scanning for *10 s and quality factor (QF) value [60 were obtained, and then the image was frozen to ensure the quality of EI images. ARFI elastography was then performed on the long axis of the nodule, which was initiated when the patient was holding the breath. ARFI involves VTI and VTQ for targeting an anatomic region to interrogate the elastic properties. For VTI, the sampling box is set to include the lesion and some surrounding thyroid tissues, and the result is represented as gray-scale image over the conventional B-mode image, in which the black indicates hard tissue and white indicates soft tissue. For VTQ, tissue at the ROI is mechanically excited using acoustic pulses, and the SWV is obtained by measuring the time to peak displacement at each lateral location. The ROI with fixed dimension of 5 mm 9 6 mm was placed inside the nodule, and cystic and calcified areas were avoided. The nodules were measured 7 times at least.
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Table 1 Basic Characteristics and US features of the patients and nodules with concurrent Hashimoto’s thyroiditis Parameters
Overall nodules
Malignant nodules
Benign nodules
No. of patients
141
71
70
No. of nodules
141
71
70
Sex (male/female)
7/134
3/68
4/66
0.687 0.027
Mean age (yrs)
50.1 ± 11.9
47.9 ± 13.0
52.4 ± 10.3
Range
(23–75)
(23–75)
(25–73)
Mean size (mm)
14.5 ± 7.7
11.6 ± 5.5
17.3 ± 8.5
Range
(5–40)
(5–31)
(5–40)
P value
0.000
Single/multiple nodules
38/103
25/46
13/57
0.027
Left/right/isthmus
71/65/5
35/33/3
36/32/2
0.750 0.071
Thickness of isthmus (mm)
3.0 ± 1.3
2.8 ± 0.9
3.2 ± 1.6
Range Echogenicity
(1.4–9.0)
(1.4–5.8)
(1.8–9.0)
1/29/59/32/20
1/1/34/31/4
0/28/25/1/16
Hyper-/iso-/hypo-/markedly hyper-/mixed-
0.008
Shape Regular/irregular
0.000 100/41
35/36
65/5
69/72
18/53
51/19
103/38
61/10
42/28
74/13/54
19/5/47
55/8/7
89/52
26/45
63/7
7/83/51
5/43/23
2/40/28
Margin Well/poorly defined
0.000
Halo sign Absent/present
0.000
Calcification No-/macro-/micro-
0.000
Height and width \1 or [1
0.000
Vascularity No-/rare-/rich internal flow
0.241
Data are means ± standard deviations No. number
After that, the ROI was moved to the surrounding thyroid tissue at the same depth and the procedure was repeated for 7 times, and surrounding SWV (SSWV) was obtained. Image interpretation All US, EI and ARFI images were analyzed by two investigators independently who were blind to the pathological results. All investigators were trained before the analysis. A third senior investigator reviewed the images and made the final decision when discordance appeared for the evaluation between the two investigators. The US features of the patients were reviewed, and US stratification was made in terms of nodule size, number of nodules, position, thickness of isthmus, echogenicity, shape, margin, halo sign, calcification, height and width shape and internal vascularity. The EI score was assessed based on a color scale; the blue color was correlated with hard tissue, while red and green color with soft tissue.
Nodules were classified into four classes according to Asteria et al. [22]: EI score-1, prevalence of red and green color (soft); EI score 2, predominant green with few blue areas/spots; EI score-3, blue in at least 50 % of nodule; EI score 4, the nodule is displayed predominantly in blue (hard). The VTI grade of the thyroid lesions was thereafter classified into grade I to grade VI according to the Xu’s VTI grading system [17]: Grade I, predominantly white; Grade II, predominantly white with few black portions; Grade III, black and white portion equally; Grade IV, predominantly black with a few white spots; Grade V, almost completely black, and Grade VI, completely dark. For VTQ, the maximal and the minimal SWVs and SSWVs were eliminated and the mean of the remaining 5 measurements were calculated. The SWV ranges from 0.5 to 8.4 m/s. The values displayed as ‘‘x.xxm/s’’ indicate an invalid shear wave estimate. The mean SWV of the nodule, surrounding SWV (SSWV), and SWV ratio (SWV/SSWV) were calculated, respectively.
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Fig. 1 Images in a 54-year-old woman with papillary thyroid carcinoma and concomitant Hashimoto’s thyroiditis. (a, b) At conventional US, a 10-mm nodule in the left of the thyroid is solid, isoechogenic, poorly defined, with microcalcification and rich internal flow (arrows). At elastography, EI score of 4 (arrows) (c), VTI grade of VI (arrows) (d) and SWV of x.xx m/sec at VTQ were assigned (e). f The nodule is confirmed to be papillary thyroid carcinoma with concomitant Hashimoto’s thyroiditis pathologically. Vs shear wave velocity (SWV)
Statistical analysis Statistical analysis was performed using SPSS software (version 14.0, Chicago, IL, USA). Continuous variables were analyzed by the independent t test, while categorical variables were analyzed using nonparametric Wilcoxon– Mann–Whitney U test. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of conventional US, EI and ARFI elastography. The area under the ROC curve (AUC) and its 95 % confidence interval (CI) were calculated. A diagnostic tool is defined as perfect if the AUC is 1, excellent if the AUC is[0.9, and good if the AUROC is[0.8 [31]. The comparison of AUCs is performed by Z test. The cut-off values for SWV and SWV ratio for distinguishing malignant thyroid nodules from all nodules in HT patients were obtained at the point when Youden index (YI)
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(YI = sensitivity ? specificity - 1) was maximum [32]. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were calculated according to the diagnostic test 2 9 2 contingency tables. The Chi-squared test was used to compare the sensitivities, specificities, PPVs and NPVs and accuracies. A two-tailed P value \0.05 was statistically significant.
Results Pathological diagnosis All the 141 nodules were confirmed by surgical pathology. Of them, 71 (50.4 %) were papillary thyroid carcinomas, 31 (22.0 %) were Hashimoto nodules, 25 (17.7 %) were nodular goiters, and 14 (9.9 %) were adenomas.
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Fig. 2 Images in a 55-year-old woman with nodular goiter and concomitant Hashimoto’s thyroiditis. At conventional US, a 17-mm nodule in the right of the thyroid is solid, hypoechogenic, well defined, with halo sign and rich internal flow (arrows) (a, b). At elastography, EI score of 2 (arrows) (c), VTI grade of III (arrows) (d) and SWV of 2.03 m/sec at VTQ were assigned (e). f The nodule is confirmed to be nodular goiter with concomitant Hashimoto’s thyroiditis pathologically. Vs shear wave velocity (SWV)
Basic characteristics and conventional US features
EI and ARFI elastography
The basic characteristics and US features of the patients and nodules are presented in Table 1. The significant clinical features for differentiation between benign and malignant groups were patient age, nodule size and number of nodules (all P \ 0.05). HT patients with malignant nodules tended to be younger, and the size of malignant nodules were smaller than benign ones. Conversely, patient sex (P = 0.687), nodule position (P = 0.716) and thickness of isthmus (P = 0.071) did not achieve a significant difference between malignant and benign nodules. For US features, it was statistically different between the two groups for echogenicity, irregular shape, poorly defined margin, absence of halo sign, calcification and height/width [1 (all P \ 0.05; Figs. 1, 2).
The differences were significant between malignant and benign nodules in HT patients for EI score, VTI grade, SWV and SWV ratio (all P \ 0.05) (Table 2; Figs. 1, 2). The results of ‘‘x.xx’’ were displayed in 26 nodules, of which 22 were malignant, and remaining 4 were benign. Of the 70 benign nodules, it had no statistical difference among Hashimoto nodules (n = 31), nodular goiters (n = 25) and adenomas (n = 14) for EI score (all P [ 0.05) and VTI grade (all P [ 0.05). The mean SWV of Hashimoto nodules, nodular goiters and adenomas were 2.35 ± 0.66 m/s (range 0.81–3.58 m/s), 2.22 ± 0.90 m/ sec (range 0.89–4.16 m/s) and 2.67 ± 1.75 m/s (range 0.89–8.4 m/s) (all P [ 0.05), and all of them were significantly lower than that of malignant nodules (all P \ 0.05).
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Table 2 Comparison with EI and ARFI elastography between malignant and benign nodules in HT patients
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Parameters
Overall nodules (n = 141)
Malignant nodules (n = 71)
Benign nodules (n = 70)
EI score = 1
3 (2.1 %)
0 (0.0 %)
3 (4.3 %)
EI score = 2
50 (35.5 %)
17 (23.9 %)
33 (47.1 %)
EI score = 3
59 (41.8 %)
32 (45.1 %)
27 (38.6 %)
EI score = 4
29 (20.6 %)
22 (31.0 %)
7 (10.0 %)
Grade I
0 (0.0 %)
0 (0.0 %)
0 (0.0 %)
Grade II
16 (11.3 %)
1 (1.4 %)
15 (21.4 %)
Grade III
53 (37.6 %)
7 (9.9 %)
46 (65.7 %)
Grade IV Grade V
43 (30.5 %) 28 (19.9 %)
36 (50.7 %) 26 (36.6 %)
7 (10.0 %) 2 (2.9 %)
1 (0.7 %)
1 (1.4 %)
0 (0.0 %)
3.37 ± 2.16
4.36 ± 2.51
2.37 ± 1.04
0.81–8.40
1.67–8.40
0.81–8.40
P value \0.001*
EI
ARFI \0.001*
VTI
vGrade VI EI elasticity imaging; ARFI acoustic radiation force impulse, VTI virtual touch tissue imaging, VTQ virtual touch tissue quantification, SWV shear wave velocity, SSWV surrounding shear wave velocity * indicates statistically significant difference
VTQ SWV (m/s) Range SSWV (m/s)
2.28 ± 0.63
2.30 ± 0.63
2.26 ± 0.63
Range
0.89–4.42
0.89–4.30
0.95–4.42
SWV ratio
1.60 ± 1.30
2.08 ± 1.60
1.12 ± 0.57
Range
0.24–9.44
0.64–9.44
0.24–3.46
No statistical differences were found for SWV ratio among Hashimoto nodules (mean 1.14 ± 0.49; range 0.49–3.40), nodular goiters (mean 0.99 ± 0.51; range 0.24–2.70) and adenomas (mean 1.29 ± 0.79; range 0.42–3.46) (all P [ 0.05). Diagnostic performance The sensitivity, specificity, PPV, NPV, accuracy, AUC and its 95 % CI for conventional US, EI and ARFI elastography are presented in Table 3. The highest diagnostic accuracy and AUC for US features were found in microcalcification (78.0 %, 0.78), followed by height/width [ 1 (76.6 %, 0.77). Absence of halo sign had a high sensitivity (85.9 %), whereas a poor specificity (40.0 %); markedly hypoechogenicity had a high specificity (98.6 %), whereas a poor sensitivity (43.7 %). The AUC for VTI was 0.90 (95 % CI: 0.84–0.95), which was significantly higher than 0.68 (95 % CI: 0.59–0.77) for EI (P \ 0.001), 0.77 (95 %CI: 0.70–0.85) for SWV (P = 0.005) and 0.74 (95 %CI: 0.66–0.82) for SWV ratio (P = 0.001). The cut-off points were 2.58 m/s for SWV and 1.03 for SWR. The sensitivity (88.7 %) for VTI grade was similar to EI score (88.4 %), and SWV ratio (85.9 %, P = 0.802) was higher than the sensitivity for EI (76.1 %, P = 0.077) and SWV (76.1 %, P = 0.077). In addition, VTI grade (87.1 %) had a better specificity than EI score
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\0.001* 0.666 \0.001*
(51.4 %, P = 0.000), SWV (70.0 %, P = 0.022) and SWV ratio (50.0 %, P = 0.000).
Discussion Hashimoto’s thyroiditis (HT) was the most common autoimmune inflammation disease [4, 33]. Thyroid cancer was more frequently found in HT patients than in non-HT patients [9, 10]. Furthermore, a higher prevalence of suspicious or indeterminate FNAC reports was reported when target nodule was harbored within a Hashimoto’s gland [34]. Therefore, it was important to select suspicious nodules for further management in HT patients. It was an identifiable difficulty between Hashimoto nodule and thyroid cancer with concurrent HT. In the present study, PTC was more likely to be younger, be female and be smaller nodules than benign nodules in HT patients, in accordance with the results reported by Zhang et al. [9]. However, Zhang et al. [9] only compared clinical features of PTC in HT patients from an area with a high prevalence of Hashimoto’s disease; they did not evaluate conventional US and elastography image features. US, with advantages of low cost, convenience and without radiation, has become the most widely used examination method in thyroid disease. The sensitivities for US features in our study ranged from 43.7 to 85.9 %, and specificity
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Table 3 The diagnostic performance between malignant and benign nodules for US features, EI and ARFI elastography Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
Accuracy (%)
AUC (95 % CI)
US features Hypoechogenicity Markedly hypoechogenicity
47.9
64.3
57.6
54.9
56.0
0.55
(34/71)
(45/70)
(34/59)
(45/82)
(79/141)
(0.46–0.65)
43.7
98.6
96.9
63.3
70.9
0.72
(31/71)
(69/70)
(31/32)
(69/109)
(100/141)
(0.63–0.80)
50.7
92.9
87.8
65.0
71.6
0.73
(36/71)
(65/70)
(36/41)
(65/100)
(101/141)
(0.64–0.81)
74.6
72.9
73.6
73.9
73.8
0.74
(53/71)
(51/70)
(53/72)
(51/69)
(104/141)
(0.65–0.82)
Absent of halo sign
85.9
40.0
59.2
73.7
63.1
0.71
Microcalcification
(61/71) 66.2
(28/70) 90.0
(61/103) 87.0
(28/38) 72.4
(89/141) 78.0
(0.62–0.80) 0.78
(47/71)
(63/70)
(47/54)
(63/87)
(110/141)
(0.70–0.86)
63.4
90.0
86.5
70.8
76.6
0.77
(45/71)
(63/70)
(45/52)
(63/89)
(108/141)
(0.69–0.85)
Irregular shape Poorly defined margin
Height/width [1 Elastography EI score C3
76.1
51.4
61.4
67.9
63.8
0.68
(54/71)
(36/70)
(54/88)
(36/53)
(90/141)
(0.59–0.77)
88.7
87.1
87.5
88.4
87.9
0.90
(63/71)
(61/70)
(63/72)
(61/69)
(124/141)
(0.84–0.95)
76.1
70.0
72.0
74.2
73.0
0.77
(54/71)
(49/70)
(54/75)
(49/66)
(103/141)
(0.70–0.85)
85.9
50.0
63.5
77.8
68.1
0.74
(61/71)
(35/70)
(61/96)
(35/45)
(96/141)
(0.66–0.82)
ARFI VTI grade C4 SWV C2.58 m/s SWV ratio C1.03
US ultrasound, EI elasticity imaging, ARFI acoustic radiation force impulse, VTI, virtual touch tissue imaging, SWV shear wave velocity, PPV positive predictive value, NPV negative predictive value, AUC area under curve, CI confidence interval
ranged 40.0 to 98.6 %. Several US features were significantly different between malignant and benign nodules in HT patients (Table 1). However, no US features had a good sensitivity and specificity simultaneously. EI was performed in some studies for diagnosing malignant thyroid nodules from overall nodules, which is an imaging technique to directly reveal the physical property of tissue with conventional US probes by representing as color-coded images [16, 17, 25]. A meta-analysis about conventional elastography reported a sensitivity and specificity of 92 and 90 %, respectively [24]. For HT, the chronic autoimmune lymphocytic infiltration and fibrosis were able to change the stiffness of the tissue. The sensitivity, specificity and AUC for EI score C3 were 76.1, 51.4 % and 0.68 (95 %CI: 0.59–0.77), respectively, in the current study. They were slightly lower than the study reported by S¸ ahin et al. [28], which evaluated elastography in the differential diagnosis of thyroid nodules in HT, with sensitivity, specificity and AUC of 82.6, 50.9 % and 0.75 (95 %CI: 0.64–0.87).
To the best of our knowledge, this is the first study investigating the diagnostic performance of ARFI elastography for HT patients of thyroid nodules in comparison with EI and conventional US. In the current study, ARFI elastography had a better diagnostic performance than EI and conventional US. ARFI elastography has been reported to be a powerful tool for the diagnosis of malignant thyroid nodules [16, 17, 26]. For VTI grade, the sensitivity, specificity, PPV, NPV, accuracy and AUC were 88.7, 87.1, 87.5, 88.4, 87.9 % and 0.90 (95 % CI: 0.84–0.95), respectively. They were similar to the study reported by Zhang et al. in a general population [26], with the sensitivity, specificity and accuracy of 87.0, 95.8 and 92.7 % for VTI in differentiating malignant from benign thyroid nodules, which indicates that the diagnostic performance of VTI is not influenced by the thyroid background. The mean SWV of malignant and benign nodules in HT patients was 4.36 ± 2.51 m/s and 2.37 ± 1.04 m/s, which were higher than the study reported by Han et al. [27], with 3.32 ± 0.77 m/s and 2.13 ± 0.32 m/s in HT patients. Nonetheless, the mean SWVs of malignant nodules
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were higher than that of benign ones in both studies. However, VTI of ARFI and EI were not included for evaluation in Han’s study [27]. The cut-off SWV of VTQ for diagnosing malignant nodules in HT patients was 2.58 m/s, which was similar to that in general populations that the cut-off value ranged from 2.42 m/s to 2.87 m/s [16, 17, 35–37]. The cutoff SWV ratio was 1.03 which was lower than 1.59 reported by previous study [16]; the underlying mechanism of which might be that the surrounding thyroid tissue was harder in HT than in non-HT, and the thyroid parenchyma was inhomogeneous [4, 29, 38]. However, it had no significant difference in surrounding SWV between malignant and benign nodules in HT patients in accordance with most known studies [27, 29]. There were several limitations in the study. Firstly, only pathologically proven nodules with HT were analyzed; thus, selection bias may be present, and the results should be carefully interpreted. Secondly, serological indicators (TgAb and TPOAb) and thyroid function in HT patients were not included in the study. In addition, it was a single-center study, and the case number was not high enough. Further multicenter studies with large case series are mandatory. In summary, the present study demonstrates that ARFI elastography is a useful tool in indentifying malignant nodules in HT patients. Specifically, VTI application of ARFI has the highest diagnostic performance in comparison with conventional US, EI and VTQ of ARFI. 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 2012045 from Shanghai Municipal Human Resources and Social Security Bureau and Grant 81401417 from the National Natural Science Foundation of China. Conflict of interest
The authors declare no conflict of interest.
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7. Ezzat S, Sarti DA, Cain DR, Braunstein GD. Thyroid incidentalomas: prevalence by palpation and ultrasonography. Arch Intern Med. 1994;154:1838–40. 8. Konturek A, Barczynski M, Wierzchowski W, Stopa M, Nowak W. Coexistence of papillary thyroid cancer with Hashimoto thyroiditis. Langenbecks Arch Surg. 2013;398:389–94. 9. Zhang L, Li H, Ji QH, Zhu YX, Wang ZY, Wang Y, Huang CP, Shen Q, Li DS, Wu Y. The clinical features of papillary thyroid cancer in Hashimoto’s thyroiditis patients from an area with a high prevalence of Hashimoto’s disease. BMC Cancer. 2012; 12:610. 10. Kim KW, Park YJ, Kim EH, Park SY, Park do J, Ahn SH, Park do J, Jang HC, Cho BY. Elevated risk of papillary thyroid cancer in Korean patients with Hashimoto’s thyroiditis. Head Neck. 2011;33:691–5. 11. Zhang Y, Dai J, Wu T, Yang N, Yin Z. The study of the coexistence of Hashimoto’s thyroiditis with papillary thyroid carcinoma. J Cancer Res Clin Oncol. 2014;140:1021–6. 12. Kim EK, Park CS, Chung WY, Oh KK, Kim DI, Lee JT, Yoo HS. New sonographic criteria for recommending fine-needle aspiration biopsy of nonpalpable solid nodules of the thyroid. AJR Am J Roentgenol. 2002;178:687–91. 13. Lee JH, Anzai Y. Imaging of thyroid and parathyroid glands. Semin Roentgenol. 2013;48:87–104. 14. Solbiati L, Osti V, Cova L, Tonolini M. Ultrasound of thyroid, parathyroid glands and neck lymph nodes. Eur Radiol. 2001;11: 2411–24. 15. Frates MC, Benson CB, Charboneau JW, Cibas ES, Clark OH, Coleman BG, Cronan JJ, Doubilet PM, Evans DB, Goellner JR, Hay ID, Hertzberg BS, Intenzo CM, Jeffrey RB, Langer JE, Larsen PR, Mandel SJ, Middleton WD, Reading CC, Sherman SI, Tessler FN. Society of radiologists in ultrasound. Management of thyroid nodules detected at US: society of radiologists in ultrasound consensus conference statement. Radiology. 2005;237:794–800. 16. Zhang YF, Xu HX, He Y, Liu C, Guo LH, Liu LN, Xu JM. Virtual touch tissue quantification of acoustic radiation force impulse: a new ultrasound elastic imaging in the diagnosis of thyroid nodules. PLoS ONE. 2012;7:e49094. 17. Xu JM, Xu XH, Xu HX, Zhang YF, Zhang J, Guo LH, Liu LN, Liu C, Zheng SG. Conventional US, US elasticity imaging, and acoustic radiation force impulse imaging for prediction of malignancy in thyroid nodules. Radiology. 2014;272:57–86. 18. Ceylan I, Yener S, Bayraktar F, Secil M. Roles of ultrasound and power Doppler ultrasound for diagnosis of Hashimoto thyroiditis in anti-thyroid marker-positive euthyroid subjects. Quant Imaging Med Surg. 2014;4:232–8. 19. Kim DW, Eun CK, In HS, Kim MH, Jung SJ, Bae SK. Sonographic differentiation of asymptomatic diffuse thyroid disease from normal thyroid: a prospective study. AJNR Am J Neuroradiol. 2010;31:1956–60. 20. Lyshchik A, Higashi T, Asato R, Tanaka S, Ito J, Mai JJ, PellotBarakat C, Insana MF, Brill AB, Saga T, Hiraoka M, Togashi K. Thyroid gland tumor diagnosis at US elastography. Radiology. 2005;237:202–11. 21. Rago T, Santini F, Scutari M, Pinchera A, Vitti P. Elastography: new developments in ultrasound for predicting malignancy in thyroid nodules. J Clin Endocrinol Metab. 2007;92:2917–22. 22. Asteria C, Giovanardi A, Pizzocaro A, Cozzaglio L, Morabito A, Somalvico F, Zoppo A. US-elastography in the differential diagnosis of benign and malignant thyroid nodules. Thyroid. 2008;18: 523–31. 23. Tranquart F, Bleuzen A, Pierre-Renoult P, Chabrolle C, Sam Giao M, Lecomte P. Elastosonography of thyroid lesions. J Radiol. 2008;89:35–9. 24. Bojunga J, Herrmann E, Meyer G, Weber S, Zeuzem S, Friedrich-Rust M. Real-time elastography for the differentiation of
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ORIGINAL PAPER
Acoustic radiation force impulse elastography for differentiation of benign and malignant thyroid nodules with concurrent Hashimoto’s thyroiditis Bo-Ji Liu • Hui-Xiong Xu • Yi-Feng Zhang • Jun-Mei Xu • Dan-Dan Li • Xiao-Wan Bo • Xiao-Long Li • Le-Hang Guo Xiao-Hong Xu • Shen Qu
•
Received: 10 January 2015 / Accepted: 23 January 2015 Ó Springer Science+Business Media New York 2015
Abstract The purpose of the study was to explore the diagnostic performance of acoustic radiation force impulse (ARFI) elastography in differential diagnosis between benign and malignant thyroid nodules in patients with coexistent Hashimoto’s thyroiditis (HT). A total of 141 pathological proven nodules in 141 HT patients (7 males and 134 females, mean age 50.1 years, range 23–75 years) received conventional ultrasound (US), elasticity imaging (EI) and ARFI elastography, including virtual touch tissue imaging (VTI) and virtual touch tissue quantification (VTQ), before surgery. Shear wave velocity (SWV) and SWV ratio were measured for each nodule on VTQ. The US, EI and ARFI elastography features were compared between benign and malignant nodules in HT patients. Receiver operating characteristic curve (ROC) analyses and area under curve (AUC) were performed to assess the
diagnostic performance. Pathologically, 70 nodules were benign and 71 nodules were malignant. Significant differences were found between benign and malignant nodules in HT patients for EI (EI score) and ARFI (VTI grade and SWV) (all P value \0.05). The AUCs for EI, VTI, SWV and SWV ratio were 0.68 [95 % confidence interval (CI): 0.59–0.77], 0.90 (95 % CI: 0.84–0.95), 0.77 (95 %CI: 0.70–0.85) and 0.74 (95 %CI: 0.66–0.82), respectively. The cut-off points were EI score C3, VTI grade C4, SWV C2.58 m/s and SWV ratio C1.03, respectively. In conclusion, ARFI elastography is useful for differentiation between benign and malignant thyroid nodules in HT patients. The diagnostic performance of ARFI elastography is better than EI.
B.-J. Liu H.-X. Xu (&) Y.-F. Zhang J.-M. Xu D.-D. Li X.-W. Bo X.-L. Li L.-H. Guo Department of Medical Ultrasound, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China e-mail: [email protected]
Introduction
B.-J. Liu H.-X. Xu Y.-F. Zhang J.-M. Xu D.-D. Li X.-W. Bo X.-L. Li L.-H. Guo S. Qu Thyroid Institute, Tongji University School of Medicine, Shanghai 200072, China H.-X. Xu X.-H. Xu Department of Ultrasound, Guangdong Medical College Affiliated Hospital, Zhanjiang 524001, China S. Qu Department of Endocrinology and Metabolism, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai 200072, China
Keywords Acoustic radiation force impulse Hashimoto’s thyroiditis Elastography Thyroid nodules
Hashimoto’s thyroiditis (HT), with an incidence of about 1 case per 1,000 persons per year [1], is a chronic autoimmune inflammation disease of the thyroid gland and now is generally considered the most common cause of hypothyroidism [2, 3]. The diagnosis of HT is usually established by the positive test for serum thyroglobulin antibody (TgAb) and/or thyroid peroxidase (TPOAb) antibody, and hypoechoic appearance for thyroid in ultrasound scan [4]. Thyroid nodules are common clinically, and the incidence is up to 50 % on ultrasound (US) examination [5]. In HT patients, some of them are true tumorous or hyperplastic nodules, while the others can be pseudo-nodules (Hashimoto nodules) when the dense fibrosis distorts the thyroid architecture and imparts to gland a lobular
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appearance in fibrous variant form of HT [6]. The clinical importance of thyroid nodules is the early detection of thyroid cancer, which has a 5 % incidence in overall thyroid nodules [7]. A higher prevalence of thyroid cancer was found in HT patients than in overall population (29.4 vs. 19.4 %), and coexisting HT for thyroid nodules increased the risk of papillary thyroid carcinoma (PTC; odds ratio value: 2.96) [8–11]. On conventional US, the echogenicity of the thyroid parenchyma in HT is usually heterogeneous since thyroid follicles are destroyed and replaced by small lymphocytes. Hypoechogenicity is considered to be one of the suspicious malignant features in thyroid nodules [12]; however, hypoechogenic appearance is common in HT patients and is always diffusely distributed in the gland. Therefore, it is difficult to diagnose malignant nodules from all nodules using conventional US in patients with coexistent HT. As a consequence of this, not few HT patients with nodules are referred to a diagnostic surgery when the fine-needle aspiration cytology (FNAC) results are indeterminate and often undergo thyroidectomy to find the pathological outcome is benign. Conventional US is the most commonly used imaging modality for thyroid diseases, the sensitivity of which in diagnosing malignant thyroid nodules ranged from 38.8 to 90.9 % in non-HT patients [12–17], while it ranged from 17.5 to 87.5 % in HT patients [18, 19]. Conventional strain elastography (SE) is a useful tool in differentiating malignant from benign thyroid nodules by enabling measurement of tissue deformation in response to compression and displaying tissue stiffness [20–23]. A metaanalysis about conventional SE reported a sensitivity and specificity of 92 and 90 %, respectively [24]. Acoustic radiation force impulse (ARFI) elastography is a further improvement in comparison with conventional SE that it could evaluate the tissue stiffness qualitatively and quantitatively. For ARFI elastography, transient pulses are used to generate propagating shear waves in the region of interest (ROI). The strain change under the push pulse is named as virtual touch tissue imaging (VTI), which uses an algorithm that is similar to that of conventional SE and is displayed as a gray-scale image. Quantitative evaluation of the tissue stiffness is named as virtual touch tissue quantification (VTQ) by calculating the shear wave velocity (SWV). The usefulness of ARFI elastography in diagnosis of thyroid nodules in general population has been confirmed by several studies [16, 17, 25, 26], whereas its usefulness in HT patients lacked sufficient evidences because of potential change of stiffness caused by lymphocyte infiltration, fibrosis and parenchyma atrophy [27–30]. In the present study, the diagnostic performance of ARFI elastography for identifying thyroid malignancy in a consecutive series of HT patients was evaluated.
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Materials and methods Patients The study was approved by the Ethical Committee of the university hospital, and informed consent was obtained from all patients. T total of 2,000 consecutive patients were examined by conventional US, conventional SE of elasticity imaging (EI) and ARFI elastography from January 2013 to September 2014. All the patients had thyroid nodules on conventional US, and the nodule diameter was not\5 mm. The patients were excluded when they met one of the following criteria: (1) patients had previous history of surgery (n = 136); (2) completely cystic or almost cystic ([50 %) appearance at conventional US (n = 85); (3) incomplete data for conventional US, EI or ARFI images (n = 68); (3) nodules that did not have pathologic confirmation (n = 1,049); and (4) pathologic outcome of the thyroid background was not concurrent HT (n = 521). When multiple nodules existed, the most suspicious one on US or the largest one was selected for examination. Finally, 141 nodules from 141 HT patients (7 males and 134 females, mean age 50.1 ± 11.9 years, range 23–75 years) were included. Conventional US, EI and ARFI Elastography Conventional US, EI and ARFI examinations were performed using the same S2000 US scanner (Siemens Medical Solutions, Mountain View, Calif, USA) with a 4–9 MHz linear transducer. The patients were positioned in supine position with dorsal flexion of the head. B-mode US and color Doppler US were performed, and the maximal diameter of the nodule was measured. EI was performed following conventional US by the same investigator. The transducer was placed on the body surface, and a light pressure was applied. Continuous scanning for *10 s and quality factor (QF) value [60 were obtained, and then the image was frozen to ensure the quality of EI images. ARFI elastography was then performed on the long axis of the nodule, which was initiated when the patient was holding the breath. ARFI involves VTI and VTQ for targeting an anatomic region to interrogate the elastic properties. For VTI, the sampling box is set to include the lesion and some surrounding thyroid tissues, and the result is represented as gray-scale image over the conventional B-mode image, in which the black indicates hard tissue and white indicates soft tissue. For VTQ, tissue at the ROI is mechanically excited using acoustic pulses, and the SWV is obtained by measuring the time to peak displacement at each lateral location. The ROI with fixed dimension of 5 mm 9 6 mm was placed inside the nodule, and cystic and calcified areas were avoided. The nodules were measured 7 times at least.
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Table 1 Basic Characteristics and US features of the patients and nodules with concurrent Hashimoto’s thyroiditis Parameters
Overall nodules
Malignant nodules
Benign nodules
No. of patients
141
71
70
No. of nodules
141
71
70
Sex (male/female)
7/134
3/68
4/66
0.687 0.027
Mean age (yrs)
50.1 ± 11.9
47.9 ± 13.0
52.4 ± 10.3
Range
(23–75)
(23–75)
(25–73)
Mean size (mm)
14.5 ± 7.7
11.6 ± 5.5
17.3 ± 8.5
Range
(5–40)
(5–31)
(5–40)
P value
0.000
Single/multiple nodules
38/103
25/46
13/57
0.027
Left/right/isthmus
71/65/5
35/33/3
36/32/2
0.750 0.071
Thickness of isthmus (mm)
3.0 ± 1.3
2.8 ± 0.9
3.2 ± 1.6
Range Echogenicity
(1.4–9.0)
(1.4–5.8)
(1.8–9.0)
1/29/59/32/20
1/1/34/31/4
0/28/25/1/16
Hyper-/iso-/hypo-/markedly hyper-/mixed-
0.008
Shape Regular/irregular
0.000 100/41
35/36
65/5
69/72
18/53
51/19
103/38
61/10
42/28
74/13/54
19/5/47
55/8/7
89/52
26/45
63/7
7/83/51
5/43/23
2/40/28
Margin Well/poorly defined
0.000
Halo sign Absent/present
0.000
Calcification No-/macro-/micro-
0.000
Height and width \1 or [1
0.000
Vascularity No-/rare-/rich internal flow
0.241
Data are means ± standard deviations No. number
After that, the ROI was moved to the surrounding thyroid tissue at the same depth and the procedure was repeated for 7 times, and surrounding SWV (SSWV) was obtained. Image interpretation All US, EI and ARFI images were analyzed by two investigators independently who were blind to the pathological results. All investigators were trained before the analysis. A third senior investigator reviewed the images and made the final decision when discordance appeared for the evaluation between the two investigators. The US features of the patients were reviewed, and US stratification was made in terms of nodule size, number of nodules, position, thickness of isthmus, echogenicity, shape, margin, halo sign, calcification, height and width shape and internal vascularity. The EI score was assessed based on a color scale; the blue color was correlated with hard tissue, while red and green color with soft tissue.
Nodules were classified into four classes according to Asteria et al. [22]: EI score-1, prevalence of red and green color (soft); EI score 2, predominant green with few blue areas/spots; EI score-3, blue in at least 50 % of nodule; EI score 4, the nodule is displayed predominantly in blue (hard). The VTI grade of the thyroid lesions was thereafter classified into grade I to grade VI according to the Xu’s VTI grading system [17]: Grade I, predominantly white; Grade II, predominantly white with few black portions; Grade III, black and white portion equally; Grade IV, predominantly black with a few white spots; Grade V, almost completely black, and Grade VI, completely dark. For VTQ, the maximal and the minimal SWVs and SSWVs were eliminated and the mean of the remaining 5 measurements were calculated. The SWV ranges from 0.5 to 8.4 m/s. The values displayed as ‘‘x.xxm/s’’ indicate an invalid shear wave estimate. The mean SWV of the nodule, surrounding SWV (SSWV), and SWV ratio (SWV/SSWV) were calculated, respectively.
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Fig. 1 Images in a 54-year-old woman with papillary thyroid carcinoma and concomitant Hashimoto’s thyroiditis. (a, b) At conventional US, a 10-mm nodule in the left of the thyroid is solid, isoechogenic, poorly defined, with microcalcification and rich internal flow (arrows). At elastography, EI score of 4 (arrows) (c), VTI grade of VI (arrows) (d) and SWV of x.xx m/sec at VTQ were assigned (e). f The nodule is confirmed to be papillary thyroid carcinoma with concomitant Hashimoto’s thyroiditis pathologically. Vs shear wave velocity (SWV)
Statistical analysis Statistical analysis was performed using SPSS software (version 14.0, Chicago, IL, USA). Continuous variables were analyzed by the independent t test, while categorical variables were analyzed using nonparametric Wilcoxon– Mann–Whitney U test. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the diagnostic performance of conventional US, EI and ARFI elastography. The area under the ROC curve (AUC) and its 95 % confidence interval (CI) were calculated. A diagnostic tool is defined as perfect if the AUC is 1, excellent if the AUC is[0.9, and good if the AUROC is[0.8 [31]. The comparison of AUCs is performed by Z test. The cut-off values for SWV and SWV ratio for distinguishing malignant thyroid nodules from all nodules in HT patients were obtained at the point when Youden index (YI)
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(YI = sensitivity ? specificity - 1) was maximum [32]. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy were calculated according to the diagnostic test 2 9 2 contingency tables. The Chi-squared test was used to compare the sensitivities, specificities, PPVs and NPVs and accuracies. A two-tailed P value \0.05 was statistically significant.
Results Pathological diagnosis All the 141 nodules were confirmed by surgical pathology. Of them, 71 (50.4 %) were papillary thyroid carcinomas, 31 (22.0 %) were Hashimoto nodules, 25 (17.7 %) were nodular goiters, and 14 (9.9 %) were adenomas.
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Fig. 2 Images in a 55-year-old woman with nodular goiter and concomitant Hashimoto’s thyroiditis. At conventional US, a 17-mm nodule in the right of the thyroid is solid, hypoechogenic, well defined, with halo sign and rich internal flow (arrows) (a, b). At elastography, EI score of 2 (arrows) (c), VTI grade of III (arrows) (d) and SWV of 2.03 m/sec at VTQ were assigned (e). f The nodule is confirmed to be nodular goiter with concomitant Hashimoto’s thyroiditis pathologically. Vs shear wave velocity (SWV)
Basic characteristics and conventional US features
EI and ARFI elastography
The basic characteristics and US features of the patients and nodules are presented in Table 1. The significant clinical features for differentiation between benign and malignant groups were patient age, nodule size and number of nodules (all P \ 0.05). HT patients with malignant nodules tended to be younger, and the size of malignant nodules were smaller than benign ones. Conversely, patient sex (P = 0.687), nodule position (P = 0.716) and thickness of isthmus (P = 0.071) did not achieve a significant difference between malignant and benign nodules. For US features, it was statistically different between the two groups for echogenicity, irregular shape, poorly defined margin, absence of halo sign, calcification and height/width [1 (all P \ 0.05; Figs. 1, 2).
The differences were significant between malignant and benign nodules in HT patients for EI score, VTI grade, SWV and SWV ratio (all P \ 0.05) (Table 2; Figs. 1, 2). The results of ‘‘x.xx’’ were displayed in 26 nodules, of which 22 were malignant, and remaining 4 were benign. Of the 70 benign nodules, it had no statistical difference among Hashimoto nodules (n = 31), nodular goiters (n = 25) and adenomas (n = 14) for EI score (all P [ 0.05) and VTI grade (all P [ 0.05). The mean SWV of Hashimoto nodules, nodular goiters and adenomas were 2.35 ± 0.66 m/s (range 0.81–3.58 m/s), 2.22 ± 0.90 m/ sec (range 0.89–4.16 m/s) and 2.67 ± 1.75 m/s (range 0.89–8.4 m/s) (all P [ 0.05), and all of them were significantly lower than that of malignant nodules (all P \ 0.05).
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Table 2 Comparison with EI and ARFI elastography between malignant and benign nodules in HT patients
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Parameters
Overall nodules (n = 141)
Malignant nodules (n = 71)
Benign nodules (n = 70)
EI score = 1
3 (2.1 %)
0 (0.0 %)
3 (4.3 %)
EI score = 2
50 (35.5 %)
17 (23.9 %)
33 (47.1 %)
EI score = 3
59 (41.8 %)
32 (45.1 %)
27 (38.6 %)
EI score = 4
29 (20.6 %)
22 (31.0 %)
7 (10.0 %)
Grade I
0 (0.0 %)
0 (0.0 %)
0 (0.0 %)
Grade II
16 (11.3 %)
1 (1.4 %)
15 (21.4 %)
Grade III
53 (37.6 %)
7 (9.9 %)
46 (65.7 %)
Grade IV Grade V
43 (30.5 %) 28 (19.9 %)
36 (50.7 %) 26 (36.6 %)
7 (10.0 %) 2 (2.9 %)
1 (0.7 %)
1 (1.4 %)
0 (0.0 %)
3.37 ± 2.16
4.36 ± 2.51
2.37 ± 1.04
0.81–8.40
1.67–8.40
0.81–8.40
P value \0.001*
EI
ARFI \0.001*
VTI
vGrade VI EI elasticity imaging; ARFI acoustic radiation force impulse, VTI virtual touch tissue imaging, VTQ virtual touch tissue quantification, SWV shear wave velocity, SSWV surrounding shear wave velocity * indicates statistically significant difference
VTQ SWV (m/s) Range SSWV (m/s)
2.28 ± 0.63
2.30 ± 0.63
2.26 ± 0.63
Range
0.89–4.42
0.89–4.30
0.95–4.42
SWV ratio
1.60 ± 1.30
2.08 ± 1.60
1.12 ± 0.57
Range
0.24–9.44
0.64–9.44
0.24–3.46
No statistical differences were found for SWV ratio among Hashimoto nodules (mean 1.14 ± 0.49; range 0.49–3.40), nodular goiters (mean 0.99 ± 0.51; range 0.24–2.70) and adenomas (mean 1.29 ± 0.79; range 0.42–3.46) (all P [ 0.05). Diagnostic performance The sensitivity, specificity, PPV, NPV, accuracy, AUC and its 95 % CI for conventional US, EI and ARFI elastography are presented in Table 3. The highest diagnostic accuracy and AUC for US features were found in microcalcification (78.0 %, 0.78), followed by height/width [ 1 (76.6 %, 0.77). Absence of halo sign had a high sensitivity (85.9 %), whereas a poor specificity (40.0 %); markedly hypoechogenicity had a high specificity (98.6 %), whereas a poor sensitivity (43.7 %). The AUC for VTI was 0.90 (95 % CI: 0.84–0.95), which was significantly higher than 0.68 (95 % CI: 0.59–0.77) for EI (P \ 0.001), 0.77 (95 %CI: 0.70–0.85) for SWV (P = 0.005) and 0.74 (95 %CI: 0.66–0.82) for SWV ratio (P = 0.001). The cut-off points were 2.58 m/s for SWV and 1.03 for SWR. The sensitivity (88.7 %) for VTI grade was similar to EI score (88.4 %), and SWV ratio (85.9 %, P = 0.802) was higher than the sensitivity for EI (76.1 %, P = 0.077) and SWV (76.1 %, P = 0.077). In addition, VTI grade (87.1 %) had a better specificity than EI score
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\0.001* 0.666 \0.001*
(51.4 %, P = 0.000), SWV (70.0 %, P = 0.022) and SWV ratio (50.0 %, P = 0.000).
Discussion Hashimoto’s thyroiditis (HT) was the most common autoimmune inflammation disease [4, 33]. Thyroid cancer was more frequently found in HT patients than in non-HT patients [9, 10]. Furthermore, a higher prevalence of suspicious or indeterminate FNAC reports was reported when target nodule was harbored within a Hashimoto’s gland [34]. Therefore, it was important to select suspicious nodules for further management in HT patients. It was an identifiable difficulty between Hashimoto nodule and thyroid cancer with concurrent HT. In the present study, PTC was more likely to be younger, be female and be smaller nodules than benign nodules in HT patients, in accordance with the results reported by Zhang et al. [9]. However, Zhang et al. [9] only compared clinical features of PTC in HT patients from an area with a high prevalence of Hashimoto’s disease; they did not evaluate conventional US and elastography image features. US, with advantages of low cost, convenience and without radiation, has become the most widely used examination method in thyroid disease. The sensitivities for US features in our study ranged from 43.7 to 85.9 %, and specificity
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Table 3 The diagnostic performance between malignant and benign nodules for US features, EI and ARFI elastography Sensitivity (%)
Specificity (%)
PPV (%)
NPV (%)
Accuracy (%)
AUC (95 % CI)
US features Hypoechogenicity Markedly hypoechogenicity
47.9
64.3
57.6
54.9
56.0
0.55
(34/71)
(45/70)
(34/59)
(45/82)
(79/141)
(0.46–0.65)
43.7
98.6
96.9
63.3
70.9
0.72
(31/71)
(69/70)
(31/32)
(69/109)
(100/141)
(0.63–0.80)
50.7
92.9
87.8
65.0
71.6
0.73
(36/71)
(65/70)
(36/41)
(65/100)
(101/141)
(0.64–0.81)
74.6
72.9
73.6
73.9
73.8
0.74
(53/71)
(51/70)
(53/72)
(51/69)
(104/141)
(0.65–0.82)
Absent of halo sign
85.9
40.0
59.2
73.7
63.1
0.71
Microcalcification
(61/71) 66.2
(28/70) 90.0
(61/103) 87.0
(28/38) 72.4
(89/141) 78.0
(0.62–0.80) 0.78
(47/71)
(63/70)
(47/54)
(63/87)
(110/141)
(0.70–0.86)
63.4
90.0
86.5
70.8
76.6
0.77
(45/71)
(63/70)
(45/52)
(63/89)
(108/141)
(0.69–0.85)
Irregular shape Poorly defined margin
Height/width [1 Elastography EI score C3
76.1
51.4
61.4
67.9
63.8
0.68
(54/71)
(36/70)
(54/88)
(36/53)
(90/141)
(0.59–0.77)
88.7
87.1
87.5
88.4
87.9
0.90
(63/71)
(61/70)
(63/72)
(61/69)
(124/141)
(0.84–0.95)
76.1
70.0
72.0
74.2
73.0
0.77
(54/71)
(49/70)
(54/75)
(49/66)
(103/141)
(0.70–0.85)
85.9
50.0
63.5
77.8
68.1
0.74
(61/71)
(35/70)
(61/96)
(35/45)
(96/141)
(0.66–0.82)
ARFI VTI grade C4 SWV C2.58 m/s SWV ratio C1.03
US ultrasound, EI elasticity imaging, ARFI acoustic radiation force impulse, VTI, virtual touch tissue imaging, SWV shear wave velocity, PPV positive predictive value, NPV negative predictive value, AUC area under curve, CI confidence interval
ranged 40.0 to 98.6 %. Several US features were significantly different between malignant and benign nodules in HT patients (Table 1). However, no US features had a good sensitivity and specificity simultaneously. EI was performed in some studies for diagnosing malignant thyroid nodules from overall nodules, which is an imaging technique to directly reveal the physical property of tissue with conventional US probes by representing as color-coded images [16, 17, 25]. A meta-analysis about conventional elastography reported a sensitivity and specificity of 92 and 90 %, respectively [24]. For HT, the chronic autoimmune lymphocytic infiltration and fibrosis were able to change the stiffness of the tissue. The sensitivity, specificity and AUC for EI score C3 were 76.1, 51.4 % and 0.68 (95 %CI: 0.59–0.77), respectively, in the current study. They were slightly lower than the study reported by S¸ ahin et al. [28], which evaluated elastography in the differential diagnosis of thyroid nodules in HT, with sensitivity, specificity and AUC of 82.6, 50.9 % and 0.75 (95 %CI: 0.64–0.87).
To the best of our knowledge, this is the first study investigating the diagnostic performance of ARFI elastography for HT patients of thyroid nodules in comparison with EI and conventional US. In the current study, ARFI elastography had a better diagnostic performance than EI and conventional US. ARFI elastography has been reported to be a powerful tool for the diagnosis of malignant thyroid nodules [16, 17, 26]. For VTI grade, the sensitivity, specificity, PPV, NPV, accuracy and AUC were 88.7, 87.1, 87.5, 88.4, 87.9 % and 0.90 (95 % CI: 0.84–0.95), respectively. They were similar to the study reported by Zhang et al. in a general population [26], with the sensitivity, specificity and accuracy of 87.0, 95.8 and 92.7 % for VTI in differentiating malignant from benign thyroid nodules, which indicates that the diagnostic performance of VTI is not influenced by the thyroid background. The mean SWV of malignant and benign nodules in HT patients was 4.36 ± 2.51 m/s and 2.37 ± 1.04 m/s, which were higher than the study reported by Han et al. [27], with 3.32 ± 0.77 m/s and 2.13 ± 0.32 m/s in HT patients. Nonetheless, the mean SWVs of malignant nodules
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were higher than that of benign ones in both studies. However, VTI of ARFI and EI were not included for evaluation in Han’s study [27]. The cut-off SWV of VTQ for diagnosing malignant nodules in HT patients was 2.58 m/s, which was similar to that in general populations that the cut-off value ranged from 2.42 m/s to 2.87 m/s [16, 17, 35–37]. The cutoff SWV ratio was 1.03 which was lower than 1.59 reported by previous study [16]; the underlying mechanism of which might be that the surrounding thyroid tissue was harder in HT than in non-HT, and the thyroid parenchyma was inhomogeneous [4, 29, 38]. However, it had no significant difference in surrounding SWV between malignant and benign nodules in HT patients in accordance with most known studies [27, 29]. There were several limitations in the study. Firstly, only pathologically proven nodules with HT were analyzed; thus, selection bias may be present, and the results should be carefully interpreted. Secondly, serological indicators (TgAb and TPOAb) and thyroid function in HT patients were not included in the study. In addition, it was a single-center study, and the case number was not high enough. Further multicenter studies with large case series are mandatory. In summary, the present study demonstrates that ARFI elastography is a useful tool in indentifying malignant nodules in HT patients. Specifically, VTI application of ARFI has the highest diagnostic performance in comparison with conventional US, EI and VTQ of ARFI. 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 2012045 from Shanghai Municipal Human Resources and Social Security Bureau and Grant 81401417 from the National Natural Science Foundation of China. Conflict of interest
The authors declare no conflict of interest.
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