Comparison of Virtual Touch Tissue Imaging & Quantification (VTIQ) and Virtual Touch Tissue Quantification (VTQ) for diagnosis of thyroid nodules

Abstract

OBJECTIVE: The aim of this study was to compare the diagnostic performance of Virtual Touch Tissue Imaging & Quantification (VTIQ) and Virtual Touch Tissue Quantification (VTQ) in differentiating benign from malignant thyroid nodules (TNs).

MATERIALS AND METHODS: In this study 107 TNs in 107 patients were enrolled and analyzed. All of them were detected by conventional ultrasound (US) and confirmed by fine-needle aspiration (FNA) biopsy or surgery. VTIQ and VTQ examinations were performed on each nodule. Thereafter the median and mean of shear wave speed (SWS) values in lesions on VTIQ and VTQ were computed (SWS-median and SWS-mean). With cytological results of FNA and histological results adopted as the reference standard, area under the receiver operating characteristic (AUROC) curve analysis was performed to evaluate the diagnostic efficiency of VTIQ and VTQ in differentiation of TNs.

RESULTS: Among the 107 lesions, 19 were papillary thyroid carcinomas (PTCs), 1 was medullary thyroid carcinoma (MTC) and 87 were benign. In total lesions, AUROC-median in VTIQ was significantly higher than that in VTQ (0.851 vs.0.759; p < 0.05).

CONCLUSION: VTIQ and VTQ were equivalent in diagnosing TNs when using SWS-mean, whereas VTIQ showed better performance in comparison with VTQ when using SWS-median.

Keywords

Shear wave elastography thyroid nodules ultrasound fine-needle aspiration diagnostic performance

Abbreviations

SWE

Shear wave elastography

Two-dimensional

ARFI

Acoustic radiation force impulse

VTIQ

Virtual touch tissue imaging & quantification

VTQ

Virtual touch tissue quantification

Strain elastography

Thyroid nodule

Ultrasound

FNA

Fine-needle aspiration

SWS

Shear wave speed

SWS-median

Median value of shear wave speed

SWS-mean

Mean value of shear wave speed

SP-SWS

Single-point shear wave speed

2D-SWS

Two-dimensional shear wave speed

ROI

Region of interest

PPV

Positive predictive value

NPV

Negative predictive value

95% CI

95% confidence interval

AUROC

Area under the receiver operating characteristic curve

PTC

Papillary thyroid carcinoma

PTMC

Papillary thyroid micro-carcinoma

MTC

Medullary thyroid carcinoma

BSRTC

Bethesda System for Reporting Thyroid Cytopathology

1 Introduction

In general population, the incidence of thyroid nodules is increasing, which is close to 33–68%, and approximately 5–15% of these thyroid nodules are malignant [6, 26]. Thyroid carcinoma is one of the common endocrine-associated cancers and its prevalence has raised 2.4–3 folds in recent 20 years [22, 24]. Ultrasound (US) imaging which offers prominent visualization of TNs through real-time scanning is a convenient tool in detecting malignant thyroid nodules. However, US imaging alone offers insufficient information about the mechanical properties of malignant and benign TNs [9]. With an aim to further improve the diagnostic efficiency of thyroid carcinoma, elastography has been introduced into the clinic. As a noninvasive and additional imaging modality, elastography which was originally proposed to evaluate the stiffness of tissue by Ophir et al. in 1991 [21] has been widely used in recent years. Several studies had demonstrated that adding elastography to conventional US improves the differentiation of thyroid lesions [31 , 34]. Based upon the principle that under compression localized tissue displacement is more in softer tissue than in harder one, elastography can be applied to estimate the tissue stiffness so as to reflect the nature of thyroid lesions. And the increase in hardness of tissue has been verified to be associated with a raising risk of malignancy [2, 23]. Nowadays, in the process of development for elastography, it has experienced two major kinds of techniques. The first modality is strain elastography (SE). SE displays the elastic deformation based upon displacement of tissue and requires external mechanical compression. Several studies showed that SE can display color-coded images over the conventional US imaging and plays a significant role in the differentiation of TNs before fine needle aspiration (FNA) biopsy [8, 18]. Whereas, several limitations of SE are shown as follows: (1) SE can only offer semi-quantitative or qualitative information, which lacks of the quantification images to precisely calculate shear wave speed (SWS); (2) SE is operator dependent, which needs manual compression with external press and requires practice for optimal results [32]; (3) the amount of strain is depth dependent, and the degree of stress is greater at tissue with shallow depth than at that with deep depth. Thus the application of SE in the diagnosis of thyroid lesions is controversial in recent years [16]. The second modality is shear wave elastography (SWE). Compared with SE, SWE is more reproducible and less operator-dependent without reliance on external force. Nightingale et al. [20] reported the first application of in vivo and ex vivo acoustic radiation force shear wave imaging. Based upon shear wave propagation generated from acoustic radiation force, SWE can quantitatively measure the values of SWS which can be expressed in kPa or m/s. As a point SWE technique, Virtual touch tissue quantification (VTQ; Siemens Medical Solutions, Mountain View, CA, USA) is the first generation acoustic radiation force impulse (ARFI)-generated quantitative technique. As a single-point shear wave speed (SP-SWS) measurement, VTQ can calculate the SWS of tissues by scaling the time to peak displacement at every lateral location. Expressed in m/s (range, 0–8.4 m/s), the SWS is faster in harder tissue than in softer tissue. Several recent publications showed that VTQ is an additional and useful tool in the prediction of malignant TNs [10 , 36]. At present, in addition to point SWE technique, some two-dimensional (2D) SWE techniques such as SWE from Supersonic Imaging (SSI) and virtual touch tissue imaging & quantification (VTIQ; Siemens Medical Solutions, Mountain View, CA, USA) have been applied and used in clinical practice. SWE with Supersonic Imagine (SSI) can estimate stiffness of tissue in kPa with promising result [28]. As a two-dimensional shear wave speed (2D-SWS) measurement in which the SWS value is also expressed in m/s like VTQ, VTIQ can display color-coded images and measure localized SWS from 0.5 to 10 m/s using up to 256 spatial distributions of ARFI push and pulse beams [3 , 27]. As is known to us, VTIQ and VTQ are two types of ARFI-generated quantitative techniques. Nevertheless, so far no publications about the comparison of VTIQ and VTQ have been reported, especially with regard to thyroid lesions. This study was undertaken to compare the diagnostic performance of VTIQ and VTQ for differentiation of thyroid nodules.

2 Materials and methods

2.1 Patient enrollment

This study was approved by the institutional review board and informed consent was acquired from all participating patients to include their data for analysis. From September 2014 to July 2015, a total of 802 consecutive patients with TNs which were detected by conventional US underwent both VTIQ and VTQ examinations in the university hospital. The inclusion criteria were as follows: (a) the nodules were at least 5 mm in maximal diameter and suspicious for malignancy in US; (b) solid TNs or almost solid (<25% cystic); (c) no invasive treatment such as FNA or ablation was previously performed on the nodules; (d) with adequate thyroid tissue surrounding the nodule at the same depth; (e) with cytological or pathological confirmation by FNA or surgery. For patients with multiple nodules, we selected the nodule which was most suspicious for malignancy based upon the features in US or the largest nodule when no suspicious US features were detected. Finally, pathological confirmation was obtained in 117 nodules in 117 patients. The exclusion criteria were as follows: (a) poor shear wave quality (n = 6); (b) image incompleteness (n = 4). Ultimately, a total of 107 thyroid nodules in 107 patients were included in this study (Fig. 1).

2.2 Measurement protocol of VTIQ

Before VTIQ and VTQ examinations, all nodules underwent a comprehensive conventional US examination using a linear transducer with the frequency which is above 10 MHz. The examination of VTIQ was carried out after the target lesion was determined by conventional US. VTIQ examination was performed with the Acuson S3000 US system (Siemens Medical Solutions, Mountain View, CA, USA) with a 4–9-MHz linear transducer. All examinations were performed by a radiologist who had more than 2 years of experience in thyroid US and elastography. All patients were scanned in a supine position, with necks slightly extended. Afterward, the transducer was gently applied together with a sufficient amount of couplant and perpendicularly placed to the target lesion with slight pressure so as to minimize compression distortion by the probe. Patients were asked not to breathe or swallow for a few seconds while the shear wave images were obtained. The SW-quality map, a 2D-color image, which indicates whether the shear wave has adequate signal-to-noise ratio (SNR) and magnitude, can be initially acquired to assess the quality of SW-velocity map [27]. In the SW-quality map, green represents high quality, yellow and red are respectively for moderate and low quality. Thereafter, the SW-velocity map was obtained to display SWS distribution in 2D-colour imaging. The gradual colors of SW-velocity map display the SWS from high (red), moderate (yellow or green), and to low (blue) (Fig. 2). The SWS values were then measured by placing a small region of interest (ROI) box for which the square is around 2 mm×2 mm in the SW-velocity map. As regard to the placement of ROI in the SW-velocity map, those influencing factors such as calcification, cystic portions or surrounding thyroid tissue of lesions which might confound the results of SWS measurement were avoided. Regarding to the lesions with particularly necrosis, the necrosis part was mostly displayed cystic change on US imaging. And we should place the ROI box in the solid area and tried to avoid the necrosis portion as far as possible. Moreover, the portion corresponding to low SW quality (i.e. red area on the SW-quality map) was avoided to ensure the reliability of SWS measurement. Seven measurements of SWS were performed for each lesion. When stiffness distribution of lesion was homogeneous, the seven ROI boxes on the SW-velocity map were placed at random. When stiffness distribution of lesion was heterogeneous, two SWS boxes were placed on the softest area and the hardest area respectively, and the other five ROI boxes were randomly placed in the remaining positions. Thereafter the SWS values were obtained to compute SWS-median and SWS-mean for the following comparison with VTQ.

2.3 Measurement protocol of VTQ

For VTQ examination, the measuring system used by the same radiologist, patient position, probe location and transducer condition were the same as those for VTIQ (Figs. 3 and 4). With SWS, VTQ can also display the elasticity of tissues quantitatively. The fixed dimension of ROI for VTQ is 6 mm×5 mm which cannot be altered and thus only suitable for nodules >5 mm in diameter. The ROI was placed inside the nodule, and the calcified, cystic and necrosis portions were avoided as far as possible. The measurement of SWS on each lesion was repeated for seven times. Thereafter the SWS values were obtained to compute the value of SWS-median and SWS-mean for analysis. The measurement result of “X.XX m/s” was displayed on occasion, which indicated that the stiffness of target tissue was either extraordinarily soft or extraordinarily hard. After excluding possible influencing factors such as patient movement, inappropriate ROI placement, or inappropriate compression strength, the value of “X.XX m/s” was allocated to be 8.4 m/s or 0 m/s, with 8.4 m/s and 0 m/s corresponding to the solid and cystic portion respectively. In this study, since all nodules included were solid or almost solid, “X.XX m/s” was replaced by 8.4 m/s.

2.4 Statistical analysis

All statistical analyses were performed with the SPSS 17.0 software (SPSS, Chicago, IL) and MedCalc (Mariakerke, Belgium) software. The total nodules were divided into two subgroups according to size: group 1: maximum diameter, ≤10 mm; group 2: maximum diameter, >10 mm. Means and standard deviations were used for continuous data while counts and percentages for categorical data. The differences of SWS values between benign and malignant TNs, as well as between VTIQ and VTQ were performed with independent-samples or paired-samples t test. The SWS values referring to pathological results were collected to construct receiver operating characteristic curve (ROC) in order to acquire area under ROC (AUROC), cut-off values, sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV). Comparisons of AUROC were performed at two levels: at the horizontal level, the comparisons between two SWS indices (SWS-median and SWS-mean) of VTIQ or VTQ and at the vertical level, the comparisons between VTIQ and VTQ using the SWS indices. Comparisons of AUROC were also conducted in the subgroups. Comparisons of AUROC were estimated by a univariate Z score test. The AUROC corresponding to the two SWS indices could be respectively expressed in AUROC-median and AUROC-mean. In this study, statistical significance was assigned at a two-tailed p value <0.05.

3 Results

3.1 Basic characteristics

The included 107 patients consisted of 85 women and 22 men, with the mean age of 54.0 ± 9.4 (range, 25–74 years). The mean age was 54.4 ± 9.2 (range, 25–74 years) for female patients and 52.3 ± 10.2 (range, 34–68 years) for male patients. The diameters of TNs ranged from 6.0 mm to 41.0 mm (mean size, 13.9 ± 7.8 mm). Pathological diagnoses of thyroid lesions were confirmed by FNAB or surgery, in which 87 (81.3%) were benign lesions and 20 (18.7%) were malignant ones. For benign lesions, 26 out of 87 TNs were confirmed by surgery. 22 were nodular goiters, 3 were follicular adenomas, and 1 was Hashimoto’s nodule caused by lymphocytic thyroiditis. The remaining 61 TNs were classified into Bethesda category II [5] for which the interval time of follow-up with conventional US imaging was 6 months without ≥20% increase in at least two dimensions or >50% change in volume. For malignant lesions, all 20 TNs were confirmed by surgery. One was medullary thyroid carcinoma (MTC); the remaining 19 were papillary thyroid carcinomas (PTCs).

3.2 Diagnostic performances of VTIQ and VTQ

The values of SWS-median and SWS-mean for benign and malignant lesions in both VTIQ and VTQ were compared by lesion sizes (Table 1). For each group in VTIQ and VTQ, both SWS values of malignant lesions were significantly higher than those of benign lesions (all p < 0.01).

AUROC curves were constructed to determine the optimal cut-off values for SWS-median and SWS-mean in the differentiation of thyroid lesions. Therefore, the obtained cutoff values, sensitivity, specificity, accuracy, PPV and NPV were all based upon ROC corresponding to SWSs (Table 2).

At the horizontal level, in both VTIQ and VTQ, the comparisons of AUROC between the two SWS indices did not achieve significant differences. At the vertical level, in total lesions, the comparisons of AUROC-median between VTIQ and VTQ showed statistically significant difference (p = 0.034). There were no statistically significant differences in comparisons of SWS-mean between VTIQ and VTQ (p > 0.05) (Table 3).

For subgroups in VTQ, the comparisons of AUROC of the two SWS indices in group 2 were significantly higher than those in group 1 (p < 0.05) (Table 4). In addition, the diagnostic accuracies in smaller lesions less than 10 mm in VTQ with the SWS-median and SWS-mean were 86.5% and 88.5% respectively.

4 Discussion

With regard to preoperative evaluation of thyroid tumors, FNA and conventional US are widely used in actual clinic application. FNA is an effective and useful tool with high specificity and sensitivity [7]. Surgical resection of lesions with indeterminate results remains the mainly recommended management strategy, and the necessity for a reliable diagnostic method that helps to gain better preoperative assessment still remains. Elastography is a newly developed diagnostic tool, which can estimate tissue stiffness as indicator of malignancy. The quantitative SWE technology, in which SWS values were applied, had obtained effective diagnostic performance in detecting malignant thyroid lesions [3, 31]. As is known to us, both VTIQ and VTQ are ARFI-generated quantitative techniques, which use short-duration acoustic radiation force to excite displacement of localized tissue.

VTQ is the previous point SWE technique that provides SP-SWS measurements. In this study of VTQ, better performance was obtained in differentiation of thyroid lesions when using SWS-mean. In this study, the best cutoff value of SWS-mean in total lesions was 2.83 m/s, similar with 2.87 m/s reported in the previous studies [31, 35].

VTIQ is a newer 2D SWE technique that displays 2D-SWS measurements. Several clinical reports about VTIQ obtained promising diagnostic performance in detecting malignant breast lesions [17, 27]. In terms of report about VTIQ value in thyroid lesions, Azizi et al. [3] published a prospective VTIQ study and the best cut-off value of SWS-max was determined to be 3.54 m/s, which was slightly higher than the mean value of 3.01 m/s that we obtained in the current study.

Comparing the diagnostic performance of VTIQ and VTQ, VTIQ showed better performance in comparison with VTQ using SWS-median. The differences made by VTIQ and VTQ were likely to be associated with the following factors: First, using the 2D-SWS map as a reference, the SWS distribution in VTIQ was displayed in different color modes, in which the areas of various SWSs could be visualized to evaluate and calculate. Nonetheless, it lacked of matching 2D map in VTQ [3]. Second, the size of ROI box in VTIQ was smaller than that in VTQ. Compared with VTQ in which a ROI size of 6 mm×5 mm could not be altered, VTIQ calculated SWS values with an operator defined 2-mm square measurement cursor, which could put more concentration on the target area and avoid the confounded result of surrounding thyroid tissue [36]. Third, SWS values in VTQ ranged from 0 to 8.4 m/s, beyond this range, the SWS value was expressed as X.XX m/s, making it difficult to calculate the exact value of SWS. However, in VTIQ, all SWS values were countable and ranged from 0.5 to 10 m/s, indicating values in VTIQ were more precise for quantitative measurement. In this study, seven (five in group 2, two in group 1) of SWS values in VTQ for malignant thyroid lesions were uncountable, while the values in VTIQ were all countable, which ranged from 2.21 to 9.29 m/s. Fourth, compared with VTQ, measurement of SWS in VTIQ was feasible in each lesion, especially for lesion with heterogeneous stiffness distribution. The underlying reason may be that with many reduplicated acquisitions over a 2-D space, the time of shear wave propagation in VTIQ is calculated over a very short distance with an aim to minimize the consequences of scattering, refraction and attenuation caused by heterogeneity in the lesions [27]. Moreover, Lam et al. [14] found wide variation in measurement of SWS could be brought about by varying extent of pre-compression to probe, which might lead to individual difference.

In this study, in VTQ, the comparisons of AUROC of the two SWS indices in group 2 were significantly higher than those in group 1, indicating the diagnostic performance might be associated with the lesion size, with relatively high value for TNs >10 mm and relatively low value for those ≤10 mm in diameter. The reason might be that the stiffness of lesions ≤10 mm in diameter is related to pathological components. Jebreel et al. [12] reported that small malignant lesions might not display typical features of malignant carcinomas, including fibrosis of the lesion stroma, edema and a large variation in vascular diameter. In addition, some papillary thyroid micro-carcinomas(PTMCs) were in early formation stage and the micro-calcifications had not yet developed, which might explain why the stiffness of some PTMCs were exhibited as soft [34].

Besides, in group 2, 1 false negative case was resulted from the uncommon pathological type which was medullary thyroid carcinoma (MTC). As we know, PTC derives from the follicular cells of thyroid, while MTC derives from calcitonin-producing parafollicular C cells and accounts for about 3% of thyroid cancer diagnoses [1], making it difficult to obtain comprehensive elastic features of MTC. Therefore, to better diagnose MTC cases preoperatively, elastography alone might be insufficient. Kim et al. [13] reported that MTC lesions tended to be more ovoid than PTC lesions on US. Besides, Lee et al. [15] reported that lesions with MTC were likely to be slightly larger and more frequently turned cystic change compared to those with PTC. The features mentioned above were similar to the MTC case in this study, indicating the importance of conventional US assessment still remains, which could help pay attention to the potential malignancy when the result of elastography was displayed as soft. Besides, for MTC, it is necessary to combine with measurement of serum calcitonin, FNA biopsy of suspicious lesions and RET protooncogene testing. This misdiagnosis could also help to notice that the elasticity features might overlap in different pathological patterns of lesions, thus more studies with a larger sample size about elastography characterization of various types of thyroid carcinomas might be needed in the future.

In this study, two SWS indices could display more details about elastic information of thyroid lesions, compared with the previous study for VTIQ in thyroid using single SWS indice [3]. Besides, it was the first time to compare the diagnostic performance of VTIQ and VTQ in thyroid compared with the previous study for those in breast and salivary grand [19, 27].

Nevertheless, several limitations needed to be pointed out in this study. Firstly, the sample sizes studied for comparison of these two quantitative SWE techniques were small, especially in subgroups. Besides, this study was based on retrospective data, and further prospectively designed study with long-term follow-up and a larger population is needed in the future. Secondly, the population did not display a normal distribution of thyroid disease, and the suspicious lesions on US might cause selection bias. Thirdly, 61TNs were classified into Bethesda category II in this study, and false negative rate of malignancy on lesion with benign cytology diagnose is 5% [7], thus 6-month following up might be insufficient to completely exclude malignancy for FNA benign lesions. Fourthly, the interobserver variability was not estimated in this study. However, Zhou et al. [37] had reported that the VTIQ had high interobserver variability with all interclass correlation coefficient (ICC) values higher than 0.80 (0.813–0.905).

5 Conclusion

Both VTIQ and VTQ can be utilized to quantitively measure the stiffness of thyroid lesions and are useful diagnostic tools for thyroid nodules differentiation. With SWS-median, VTIQ obtained better performance in comparison with VTQ in total lesions. It might give us hints that with 2D imaging, VTIQ can provide a more intuitive and convenient approach to help clinicians guide the placement of ROI box in elastography operation. Additionally, with the shear wave (SW)-quality map, clinicians can obtain more reliable SWS result. Therefore VTIQ, as a 2D SWE technique, can help gain better diagnostic performance and improve the confidence of clinicians. The comparisons of AUROC between the two SWS indices in group 2 were significantly higher than those of the group 1 in VTQ. In the future, the necessity for studies between VTIQ and VTQ in more details still remains. Besides, several studies had reported that CEUS was applied as a new diagnostic tool to detect the micro vascularization of thyroid carcinomas [24 , 30]. Additionally, the role of conventional US imaging is undeniably crucial. In the future, it is needed to study combined performance of the elastogaphy, CEUS, and conventional US in differentiation of thyroid lesions.

Footnotes

Acknowledgments

The scientific guarantor of this publication is Hui-Xiong Xu. The authors of this manuscript declare no relationships with any companies whose products or services may be related to the subject matter of the article. This work was supported in part by Grant SHDC12014229 from Shanghai Hospital Development Center, Grants 14441900900 and 15411969000 from Science and Technology Commission of Shanghai Municipality, and Grants 81401417 and 81501475 from the National Natural Science Foundation of China. One of the authors has significant statistical expertise. Institutional Review Board approval was obtained. Informed consent was obtained from all subjects (patients) in this study. Methodology: retrospective, diagnostic study, performed at one institution.

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