Ultrasound (US) elastography has been introduced as a non-invasive technique for evaluating thyroid diseases. This paper presents a detailed description of the technical principles, peculiarities, and limitations of US elastography techniques, including strain elastography and shear-wave elastography. This review was conducted from a clinical perspective, and aimed to assess the usefulness of US elastography for thyroid diseases in specific clinical scenarios. Although its main focus is on thyroid nodules, the applications of US elastography for other thyroid diseases, such as diffuse thyroid diseases and thyroiditis, are also presented. Furthermore, unresolved questions and directions for future research are also discussed.
Palpation is a practical diagnostic technique, especially for thyroid evaluation, and the presence of a hard thyroid nodule (TN) is associated with an increased risk of malignancy. However, this assessment is subjective and relies on the experience of the examining clinician. Small and deep nodules and those contained in multinodular goiters cannot be palpated reliably. The novel technology of ultrasound (US) elastography has been referred to as "electronic palpation," because it provides a reproducible assessment of tissue consistency. US elastography was first proposed in 1991 by Ophir et al. , and was first used for thyroid applications in 2005 by Lyshchik et al. . Moreover, the use of shear-wave elastography (SWE) for diagnosing TNs was first reported in 2010 by Sebag et al. . The stiffness of a tissue is determined by the structural properties of its matrix. Pathological changes, such as the presence of a tumor or inflammation, alter the tissue composition and structure and increase the lesion stiffness . Thus, US elastography can be used to assess the mechanical features of tissue elasticity. However, the pathologies for which elastography is suitable and its mechanisms have not been completely elucidated.
TNs are frequently found and pose a clinical dilemma, because only a few TNs harbor malignancy, while the majority of TNs are benign. The standard work-up of TNs consists of a US examination and fine-needle aspiration (FNA), but both have limitations. In the long-lasting search for suitable non-invasive diagnostic methods, US elastography has emerged as an additional tool in combination with US and FNA for TN differentiation.
Recently, some authoritative clinical practice guidelines have mentioned US elastography of the thyroid. The 2015 American Thyroid Association (ATA) management guidelines  stated that US elastography may be a helpful tool for preoperative accurate risk assessment in patients. Nevertheless, it should not modify the recommendation made based on the gray-scale US evaluation. The 2016 American Association of Clinical Endocrinologists, American College of Endocrinology, and Associazione Medici Endocrinologi Medical (AACE/ACE/AME) guidelines  stated that US elastography provides stiffness information, which is complementary to grayscale findings, particularly in nodules with indeterminate US or cytologic characteristics. Moreover, FNA is recommended for nodules with increased stiffness, an intermediate-risk factor. In addition, some specialized guidelines focusing on US elastography have been developed. The 2013 European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) guidelines  stated that US elastography could be used to guide the follow-up of lesions diagnosed as benign at FNA. In 2017, the World Federation of Societies for Ultrasound in Medicine and Biology (WFSUMB)  released a guideline for the use of elastography techniques for the thyroid, with a detailed description of the procedure and its reproducibility, results, and limitations.
To provide a comprehensive overview of the current status of thyroid US elastography, elastography techniques, their clinical applications in various thyroid diseases, diagnostic performance, and influencing factors are reviewed in the present article.
Principles of US Elastography Techniques in the Thyroid
Depending on which physical quantities are measured, there are two main thyroid elastography methods in clinical practice: strain elastography (SE) and SWE (Fig. 1). They can be classified into different variants based on the excitation method (external force, internal force, and acoustic radiation force [ARF]) and how stiffness is expressed (Fig. 2).
To evaluate the relationship between compression and strain, the Young modulus (E), also known as the ratio of stress (σ) to strain (ε), has been used. E can be calculated using Eq. (1):
SE requires mechanical stress, which results in axial displacement of the tissue [8,9]. Tissue deformation from the stress is measured and visualized on a screen. The main limitations of SE are operator-dependence for the angle, strength, and duration of compression.
Two kinds of elasticity assessments can be obtained by SE. First, a visual scoring system of colors within and around the nodules can be used, with 4- and 5-point elasticity score (ES) systems. Second, two regions of interest (ROIs) are drawn over the target region and an adjacent reference region, respectively. Then, the strain ratio (SR) is automatically calculated .
SE with external force
To acquire elastographic images, free-hand compression is continuously applied by a transducer on the neck, followed by decompression (Fig. 3A) [11,12]. Tissue stiffness is displayed as a continuum of colors from red (soft) to green (medium) and blue (hard), although some machines may apply the color scale inversely. The quality of the operator's pressure is monitored by a numeric scale or a sinusoid-shaped curve with a real-time mode (Fig. 4B).
Qualitative assessment: ES
The ES is usually calculated using the 5-point Rago criteria (Fig. 5)  or the 4-point Asteria criteria (Fig. 6) , based on the predominant color pattern of the nodule. The cut-offs between 3 and 4 on the Rago scale and 2 and 3 on the Asteria scale (Fig. 4B) are widely accepted for discriminating benign and malignant nodules.
Semi-quantitative assessment: SR
Second-generation SE devices can display the SR (parenchyma-tonodule or muscle-to-nodule SR [MNSR]). If adjacent normal thyroid tissue is absent, the MNSR can be used. SR does not represent elasticity values, due to the difficulty of measuring the amount of applied stress .
SE using carotid artery pulsation
In this technique, the compression source is carotid artery (CA) pulsation, while the operator holds the probe motionless. Preand post-compression signals are tracked and strain images are generated (Fig. 3B). The hardness is expressed as the thyroid stiffness index (TSI) or the elasticity contrast index (ECI) .
Semi-quantitative assessment: TSI
In this approach, an ROI measuring 2×2 mm is used on transverse scans, in which both the thyroid and the CA are seen. The strain near the CA (the highest-strain area) is divided by the strain of the TN (the lowest-strain area). A stiff nodule yields a high index value .
SE with ARF
A method known as acoustic radiation force impulse (ARFI) imaging can image tissue deformation using focused US beams (Fig. 3C). Imaging pulses before and after application of focused ARF "push" pulses are used to monitor tissue displacement (as a measure of deformation) within the region of the push. The ARF is calculated using Eq. (2):
where F is the ARF, α is the acoustic absorption, I is the average temporal intensity of the acoustic beam, and c is the speed of sound. The same transducer is used to generate the push pulse and to monitor the resulting tissue displacement. Strain changes are displayed as a gray-scale image. A bright shade indicates relatively soft tissue, whereas a darker shade indicates relatively stiff tissue (Fig. 4C) [18,19].
Qualitative assessment: ES
A 6-point scale developed by Xu et al.  is used for ARFI imaging (Fig. 7) based on the predominant color pattern of the lesion. A cut-off between 3 and 4 is widely accepted to discriminate benign from malignant nodules (Fig. 4C).
Semi-quantitative assessment: area ratio
In ARFI imaging, the area ratio is defined as the area of the TN on ARFI imaging divided by the area on conventional US. This idea is based on the hypothesis that thyroid cancers might have infiltrative margins .
The acoustic pulses from the probe stimulate the target tissue, creating a shear wave (SW) traveling perpendicular to the conventional US waves. SWs are the transverse components of particle displacement that are rapidly attenuated by the tissue (1-10 m/sec). This transverse component is tracked and measured as a numerical value corresponding to the shear-wave speed (SWS). This speed is closely related to the Young modulus formula, in which tissue elasticity can be assessed from the SW propagation speed [8,9]. See the following Eq. (3):
where E is the Young modulus, μ is the shear modulus, ρ is the tissue density, and c is the SWS. As SWE is dependent on the production of ARF by the probe, it is operator-independent, reproducible, and quantitative.
Two methods can be used for the clinical evaluation of TNs: the point SWE (pSWE) and 2-dimensional (2-D) SWE techniques (Fig. 8).
The pSWE technique uses short-duration (around 262 microseconds) acoustic pulses that mechanically excite the tissue within an ROI of fixed size, generating localized displacements that induce a lateral SW. Although the amplitude of these SWs is minute, they can be detected with multiple laterally positioned US "tracking" beams and can be analyzed with algorithms to reconstruct the SWS by measurement of the time to peak. Elasticity is expressed as meters per second (m/sec), and a color-coded image is not displayed (Fig. 9) [21,22].
In 2-D SWE, a color-coded map of the SWS is displayed in the field of view (FOV) when it is activated. One or more adjustable-measurement ROIs can then be placed in the FOV [7,8]. 2-D SWE can be performed using the "one-shot" technique or the "real-time" technique.
"One-shot" 2-D SWE technique
The Virtual Touch Tissue Imaging and Quantification (VTIQ, Siemens Medical Systems, Mountain View, CA, USA) system is a representative means of performing the "one-shot" 2-D SWE technique. The VTIQ system can be used to measure the SWS that propagates at a number of locations around the ARFI through a detection pulse. The image is acquired by translating the focus to cover up to 256 acquisition lines within 700 milliseconds (with an elastogram box width of 38 mm). Time is needed to allow the transducer to cool before another image can be generated after acquiring an image. Compared with pSWE, VTIQ provides more precise stiffness information within TNs because of its 2-D visualization of the SWS distribution in various colors and smaller SW ROIs. A SW-quality map is available to evaluate whether SWS propagation is reliable or adequate (Fig. 10) [23,24].
The 2-D SWE technique can also be performed using a Toshiba US system (T-SWE, Toshiba Medical System, Tochigi, Japan), which uses SWs to interrogate the viscoelastic properties of tissues. These SW display maps can be viewed in a "real-time" mode; however, a higher-quality "one-shot" mode is chosen for quantitative analysis. Its unique propagation map uses contour lines to depict SW arrival times at different points in the tissue. It is designed to allow operators to better assess the suitability of one-shot acquisitions and to optimize ROI placement such that the SW ROI is generally placed on areas with parallel contour lines (Fig. 11) [25,26].
"Real-time" 2-D SWE technique
SuperSonic SWE (S-SWE; SuperSonic Imagine [SSI], Aix-en-Provence, France) uses focused ultrasonic beams (so-called pushing beams) that propagate through the entire imaging area, and ultrafast US is used to measure the velocity of the induced SWs. From these data, tissue elasticity can be quantitatively estimated. The stiffness of a particular ROI, including mean stiffness (Emean), maximal stiffness (Emax), and standard deviation, can be expressed as SWS (m/sec) or elasticity (kPa). Soft tissue is displayed in blue and hard tissue is displayed in red (Fig. 12) [27,28].
The comb-push ultrasound shear elastography (CUSE; GE Healthcare, Wauwatosa, WI, USA) device is used to apply a recently developed technique in which multiple simultaneous laterally-spaced ARF beams generate a full FOV with SWs travelling in both lateral directions. CUSE is less affected by significant SW attenuation in areas that are far from the push beam, making it more reliable and accurate for measurements of SWS. More importantly, a full FOV reconstruction of the SWS map can be obtained with only a single fast data acquisition (about 25 milliseconds). CUSE can play an important role in thyroid applications since interference from carotid pulsation (about 1-2 pulses per second) can be avoided (Fig. 13) [29,30].
Practical Clinical Applications
Diagnostic Performance for Thyroid Malignancy
US is highly sensitive for detecting TNs and good for characterizing TNs. However, no single US feature or combination thereof can reliably predict thyroid malignancy.
Diagnostic performance of elastography and the combination of elastography and conventional US
The main studies that have investigated the diagnostic performance of US elastography, including meta-analyses, are listed in Table 1 [3,19,22,23,27,28,31-46]. A meta-analysis including 639 TNs found SE to be useful for the assessment of malignancy, with an overall mean sensitivity of 92% and mean specificity of 90% . A meta-analysis of the SR method demonstrated a pooled sensitivity and specificity of 85% and 80%, respectively . The prospective DEGUM multicenter study, which enrolled 602 patients with 657 TNs (567 benign, 90 malignant) from seven centers, found that SE as an additional US tool improved the value of US for the work-up of TNs . A meta-analysis of 15 studies of SWE that included 1,867 TNs demonstrated that the pooled sensitivity and specificity of SWE were 84.3% and 88.4%, respectively . However, these findings were challenged by the results of a retrospective study of 703 nodules reporting that the sensitivity of SE measurements (15.7% for the 5-point Rago criteria, 65.4% for the 4-point Asteria criteria) was less than that of gray-scale US features (91.7%) .
In real clinical practice, US elastography is usually performed as an extension of conventional US and not as an independent test. This is supported by the results of Trimboli et al. , who reported that the combination of these two modalities resulted in a sensitivity of 97% and negative predictive value (NPV) of 97%, which was higher than using the TSI of SE alone or B-mode features alone. Most reports have stated that a combination of conventional US and elastography showed higher sensitivity than conventional US alone. In contrast, the diagnostic accuracy, specificity, and positive predictive value (PPV) were inferior to those of conventional US alone. Moon et al.  found that neither elastography nor the combination of elastography and gray-scale US showed better performance for diagnosing thyroid cancers than gray-scale US. Therefore, the clinical application of US elastography should be determined based on how much experience the operator has with both conventional US and elastography for the thyroid.
Diagnosis of papillary thyroid microcarcinoma
Some studies have reported that SE could help to differentiate between benign and malignant thyroid micronodules [48,49]. Ma et al.  conducted a study to preoperatively predict papillary thyroid microcarcinoma (PTMC) via multiparameter US, finding that conventional US combined with contrast-enhanced US and SE could improve the diagnostic accuracy of PTMC. Zhang et al. [51,52] found that pSWE had a higher specificity than conventional US in diagnosing malignant TNs, particularly PTMCs. Thus, pSWE could increase the diagnostic confidence of the readers. A study indicated that the quantitative indices of 2-D SWE were independent predictive factors for diagnosing PTMC, which provided valuable information when conventional US could not give determinate results . One study referred to the value of 2-D SWE in differentiating PTMC, as the majority of the PTMCs (5 of 9) were missed by 2-D SWE .
Differentiation of nodules with coexistent Hashimoto thyroiditis
Thyroid parenchymal stiffness is increased in patients with Hashimoto thyroiditis (HT) , but whether inflammation reduces the accuracy of elastography in nodule evaluation is still a matter of debate . SWE seemed to correctly define the elasticity of TNs independently from the coexistence of HT . For the differentiation of true nodules from pseudonodules, SE had a sensitivity of 92.9%, a specificity of 95%, a PPV and NPV of 86.7% and 97.4%, respectively, and an accuracy of 94.4%, which was better than the combination of gray-scale and Doppler US . SR proved to be slightly better than ES for the diagnosis of nodules in this disease . Liu et al.  reported that ARFI elastography was useful for predicting thyroid malignancy in HT patients, and its diagnostic performance was better than that of SE.
Role of US Elastography in Reducing Unnecessary FNAs
In order to reduce the number of unnecessary FNAs, US elastography plays a major role in determining which nodules can be followed with imaging without FNA, with a high NPV . The use of the TSI of SE might reduce the number of punctures by 60.8%  while the concomitant application of the Thyroid Imaging Reporting and Data System (TI-RADS) system and elastography might reduce the number of FNAs by 33.8% . Zhao et al.  reported that for the 37 nodules with low suspicion on conventional US imaging, 2-D SWE was able to avoid unnecessary FNA in 77.1% of benign nodules, and 3-D SWE further increased the number to 88.6%.
Recommendations for Surgery
All the meta-analyses concluded that SWE (pSWE and 2-D SWE) is a useful complement to conventional US in predicting thyroid malignancy. It was concluded that SWE can be useful in selecting patients with TNs for surgery .
Diagnostic Utility in TNs with Nondiagnostic or Indeterminate Cytology
US-guided FNA is the widely accepted next step for diagnosing TNs, as it is relatively noninvasive and shows excellent performance. Nevertheless, FNA cytology is far from being a gold standard, because it has major limitations in excluding malignancy in lesions with nondiagnostic or indeterminate cytology. Several approaches have been used to overcome these limitations, such as repeated FNA, molecular testing, and intraoperative frozen sections. However, repeating FNA and performing molecular testing both require additional costs, and intraoperative frozen sections are by definition not performed preoperatively . Preliminary results are mixed about the role of elastography in TNs with nondiagnostic or indeterminate cytology [63-70].
Diagnostic utility in TNs with nondiagnostic cytology
Although two studies have reported US elastography to be valuable in TNs with nondiagnostic cytology [63,64], conventional US also displayed good diagnostic performance. Lin et al.  proposed an effective predictive model including elastography for identifying malignant TNs in patients with nondiagnostic cytologic findings. Park et al.  proposed that observation might be considered for solid TNs with nondiagnostic cytology that have no other suspicious US features and are benign on SE using the Asteria criteria.
Diagnostic utility in TNs with indeterminate cytology
Some studies have confirmed the usefulness of qualitative and quantitative SE to predict thyroid malignancy [64,65]. However, the study of Lippolis et al.  did not confirm the usefulness of SE in the presurgical assessment of TNs with indeterminate cytology. A meta-analysis of eight studies with 486 indeterminate-cytology TNs demonstrated pooled sensitivity, specificity, and accuracy of 69%, 75%, and 73%, respectively, for SE .
Samir et al.  reported that a higher median Young modulus from the transverse plane in SWE was associated with malignancy, with an area under the curve (AUC) of 0.81 for predicting malignancy in a study of 35 patients with indeterminate follicular TNs. A preliminary study indicated that VTIQ and the Afirma gene expression classifier demonstrated similar diagnostic performance and were independent predictors of malignancy in TNs with Bethesda III/IV results . Bardet et al.  conducted a prospective dual-center study including surgically proven TNs ≥15 mm with Bethesda III-V results. The SWE parameters were similar between benign and malignant nodules. The SWE indices failed to predict malignancy in TNs with indeterminate cytology.
Overall, 10%-75% of indeterminate-cytology nodules are follicular neoplasms . SWE may be helpful in defining the extent of thyroidectomy (total or lobectomy) for follicular neoplasms . More importantly, the incidence, risk of malignancy, and clinical significance are different among each category of indeterminate cytology, including Bethesda categories III, IV, and V. Thus, it is necessary to evaluate the value of US elastography in each category of indeterminate cytology in future studies.
Prediction of Cervical Lymph Node Metastasis in Patients with Papillary Thyroid Cancer
Cervical lymph node (CLN) metastasis is associated with increased local recurrence and decreased survival in some high-risk groups. However, CLN microscopic metastases with false-negative US characteristics have been reported in up to 90% of papillary thyroid cancer (PTC) cases associated with CLN metastasis. The risk of permanent hypoparathyroidism and permanent recurrent laryngeal nerve injury is higher for thyroidectomy accompanied with CLN dissection than for total thyroidectomy alone. Thus, a reliable assessment of CLN status is important in the treatment planning and prognostic evaluation of PTC patients.
It has been reported that US elastography was helpful for predicting CLN metastasis. Xu et al.  preoperatively evaluated a consecutive series of 203 patients with 222 PTCs by US, SE, and ARFI elastography including ARFI imaging and pSWE. Using a combination of US characteristics with and without ARFI imaging, the AUC, sensitivity, and specificity were 0.803 and 0.556, 83.0% and 100%, and 77.6% and 11.2%, respectively (P<0.001). Thus, ARFI elastography showed superior performance over conventional US, particularly when combined with conventional US, in predicting CLN metastasis in PTC patients. Park et al.  retrospectively analyzed 363 patients with 363 PTCs who underwent preoperative SWE evaluations. The findings showed that Emean and Emax was associated with central lymph node (LN) metastasis and Emin was associated with lateral LN metastasis. The quantitative elasticity index of PTC on preoperative SWE in combination with gray-scale US findings might be useful for predicting CLN metastasis. However, Yoon et al.  reported that none of the histogram parameters on SE had significant associations with poor prognostic factors, including LN metastasis.
Diffuse Thyroid Diseases and Thyroiditis
Diffuse thyroid diseases
In general, HT and Graves disease (GD) are diagnosed according to clinical, laboratory, and US findings. Sporea et al.  reported that there were significant differences in pSWE between normal subjects and patients with diffuse thyroid disease (GD and HT pathology), with SWS values of 2.07±0.44 m/sec versus 2.68±0.50 m/sec, respectively. They suggested that pSWE could predict the presence of diffuse thyroid disease with sufficient diagnostic accuracy (AUC, 0.804). However, no significant difference was found between GD and HT (2.82±0.47 m/sec vs. 2.49±0.48 m/sec). pSWE seems to be unsuitable for differentiating GD and HT. Liu et al.  also found that SWE failed to differentiate HT from GD. Fukuhara et al.  found that the SWS in patients with HT (2.47±0.57 m/sec) was significantly higher than that in controls (1.59±0.41 m/sec). The AUC for HT was 0.92, and the cut-off SWS value was 1.96 m/sec. The sensitivity, specificity, and diagnostic accuracy were 90.6%, 78.7%, and 85.1%, respectively. Therefore, pSWE may be useful for diagnosing HT and assessing the degree of fibrosis in HT.
Subacute thyroiditis (SAT) is a self-limiting inflammatory process. Most patients have a history of upper respiratory tract infection and pain in the neck. On US, SAT appears as an enlargement of the affected thyroid and poorly defined focal areas of hypoechogenicity with hypovascularity. A study documented a significant difference in the stiffness of thyroid hypoechoic lesions in 18 patients with SAT between baseline (214.26±32.5 kPa, with 17 [94.4%] with an ES of IV and 1 [5.6%] with an ES of III) and at a 10-week follow-up visit after treatment (21.65±5.3 kPa, with 15 [83.3%] with an ES of I and 3 [16.7%] with an ES of II) . SAT also showed greater hardness than HT according to an SR evaluation . The ES may help to differentiate between SAT and multinodular goiter, but it is not sufficient for distinguishing SAT from thyroid cancer, due to the similarity in the degree of stiffness .
Acute thyroiditis (AT) is a rare condition often caused by bacterial infection. The US characteristics of AT are an ill-defined lesion with heterogeneous hypoechogenicity. Ruchala et al.  reported that the thyroid tissue stiffness in two women with AT was 216.6 kPa and 241.9 kPa, respectively (both with an ES of IV). After treatment, thyroid stiffness decreased to 17.93 kPa (an ES of I) and 85.348 kPa (an ES of II), respectively. Thus, elastography may be useful for monitoring the course of AT.
Riedel (chronic) thyroiditis is characterized by extremely stiff parenchyma. The hypoechoic areas are the stiffest, representing fibrosis. Slman et al.  obtained stiffness values of 143 kPa and 281 kPa by SWE in two female patients with Riedel thyroiditis.
Comparison of Different Elastography Methods
Various commercially available US elastography devices are available from different manufacturers, with corresponding variation in techniques; thus, there is a growing need to understand their principles and to compare their real-world clinical impact.
Comparisons between Different SE Evaluation Methods
A study compared SE based on 4-point ES and the SR between the nodule and the surrounding thyroid at the same depth . The diagnostic accuracy of the SR evaluation was clearly higher than that of the ES (0.88 vs. 0.79), as was the specificity.
Comparison between SE and SWE
The ability of 2-D SWE and 5-point ES in SE to discriminate 64 TNs (19 PTCs and 45 benign) in 49 patients was compared. In that study, Liu et al.  concluded that SWE is a promising tool for differentiating TNs, as the best cut-off of a mean value of 38.3 kPa yielded results comparable to those of SE, with slightly lower sensitivity and slightly higher specificity.
In another study with 158 nodules in 138 patients, Bojunga et al.  found that there was no significant difference in diagnostic accuracy for the diagnosis of malignant TNs between pSWE and 4-point ES in SE (0.69 vs. 0.74), and the combination of pSWE and SE did not improve the diagnostic accuracy.
Comparisons of Different SWE Techniques
Yang et al.  first compared VTIQ for 2-D SWE and the Virtual Touch Tissue Quantification system (VTQ, Siemens Medical Systems) for pSWE for the diagnosis of 107 TNs in 107 patients. VTIQ and VTQ were equivalent in diagnosing TNs when using SWS-mean, whereas VTIQ showed better performance than VTQ when using SWS-median.
He et al.  reported the first comparison of VTIQ and T-SWE in the diagnosis of TNs. In general, VTIQ was equivalent to T-SWE for diagnosing TNs. In clinical practice, the selection of SWS-max should be avoided in VTIQ, whereas it should be applied in T-SWE.
He et al.  also performed the first evaluation of two different 2-D SWE imaging systems (T-SWE and S-SWE), and compared their ability to distinguish malignant from benign TNs. Their study found that T-SWE was equivalent to S-SWE, with comparable and promising results for the diagnosis of TNs. In clinical applications, the selection of Emax should be recommended, both for T-SWE and for S-SWE.
Nodules with calcifications and cystic changes
Elastography cannot be performed on nodules with a calcified shell because the sound waves cannot penetrate the calcifications . Intralesional coarse calcifications may bias the stiffness of the lesion, as can peripheral calcifications [11,86]. A partially cystic character is expected to alter nodule elasticity, although the direction of this expected effect is not known [13,14]. Thus, elastography should be selectively used in TNs with calcifications and cystic changes.
Experience of the Operator
Several studies have investigated the reproducibility of elastography (Table 2) [17,21,23,44,87- 96]. SWE often shows better reproducibility than SE. Manual external compression in SE leads to operator-dependent variability. Although SWE is less operator-dependent, external pressure can affect SW propagation through insonated tissue  and operator error is the most common type source of artifacts in SWE . Thus, US elastography should be performed by experienced operators using objective parameters with a quality indicator.
Motion Artifacts (CA Pulsation)
CA pulsation generates compression and decompression movements, inducing a certain degree of variable deformations that interfere in the elastographic evaluation. Longitudinal scans should be used because they are less susceptible to effects from the CA , but if SE with the CA is used, transverse scans should be employed [4,15].
Summary and Future Directions
US elastography examinations of the thyroid are easily integrated into conventional US examinations with many high-end systems. This procedure is completely painless for the patient, and only requires a few extra minutes, with no separate patient preparation.
US elastography has the potential to distinguish benign from malignant TNs, offering non-invasive complementary information to conventional US. The main role of US elastography is to indicate which nodules may be followed up without resorting to FNA or surgery because of its high NPV. It may be particularly useful in patients who have nondiagnostic or indeterminate FNA cytology results. US elastography might be used to guide the follow-up of lesions negative for malignancy at FNA.
Despite the initial optimism about this technique, less promising results are increasingly reported. Some authors even argued that "it [is] less likely that the use of this imaging technique to study TNs will expand significantly in the near future" . Furthermore, some hold that the modulus estimates for the thyroid might be incorrect. Estimates of shear moduli based on SWS are highly dependent on boundary conditions (minimum 3-6 cm) that cannot be met in the thyroid gland. The thyroid is not homogeneous, which is another cause of inaccurate SWE measurements.
The heterogeneous results of available studies are in part due to selection bias (varying percentages of malignancy), small cohort size, and the use of non-uniform standardization of the technique (e.g., 4- or 5-point ES, stiffness index) and of the measurement method. The value of US elastography may be limited at institutions that show high diagnostic performance by highly dedicated physicians . Studies have proposed many different cut-off values, but no meta-analyses have presented average values, and no large multi-centric studies have been conducted. No method has yet been standardized for the measurement of thyroid lesion area. The role of US elastography in TNs with undefined cytology is inconsistent, and the specific role of elastography in reducing and avoiding FNA still needs future verification. Moreover, research data are still too limited to establish the definitive role of US elastography in diagnosing the various forms of thyroiditis and diffuse thyroid diseases.
The technology is still under development, and to gain widespread clinical application, further validation will be necessary, with large cohort and multi-center prospective studies with less pre-selection to evaluate different TN characteristics, uncommon pathologies, and reproducibility, with the ultimate goal of determining how US elastography can be integrated with conventional US into emerging malignant risk classification systems (e.g., TI-RADS). Moreover, standardization of US elastography techniques will be necessary [24,102].
The role of US elastography should be explored in more specific target populations. In particular, the use of US elastography in hyperfunctional TNs, multinodular goiter, and in patients with previous radioiodine therapy or surgery has not been studied enough . The role of US elastography in the management of PTMC still needs to be defined. It is not known to what extent this technology may aid in the management of positron emission tomography/computed tomography (PET/CT)-positive thyroid incidentalomas [104,105]. The value of US elastography for treatment monitoring of TN during and after radiofrequency, microwave, or laser ablation has not been studied sufficiently [106-108]. The value of US elastography-guided FNA biopsy of TNs in reducing nondiagnostic results needs to be further evaluated .
Additionally, computer-aided diagnosis (CAD) systems have been described that use different textural features and machine learning algorithms for classification. These applications may avoid possible diagnostic errors and are able to simplify, formulate, and standardize TN classification systems . More recently, deep learning has pervaded every aspect of medical image analysis. Compared with traditional machine learning methods, this method has the benefit of not requiring image feature identification and calculation as a first step; instead, features are identified as part of the learning process .
In terms of future directions of US elastography for the thyroid, it should improve the diagnostic performance of conventional US as a good adjunctive diagnostic tool . Ideally, with advances in CAD systems and deep learning, the conventional US, US elastography, and PET/CT features of nodules could be analyzed automatically and converted into an estimate of its risk for malignancy.
This work was supported in part by the National Natural Science Foundation of China (grants 81671695, 81371570, and 81725008), Shanghai Hospital Development Center (grants 16CR3061B and SHDC12014229), and the Science and Technology Commission of Shanghai Municipality (grants 16411971100 and 14441900900).
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