**2. Ultrasound of the neck**

The current recommendations regarding the stratification of risk for Thyroid nodules (TN) include a thorough anamnesis, clinical evaluation, and neck US characterization. The B-mode (2B) evaluation is performed using linear probes, with high frequency (7.5–15 MHz) for excellent details and a resolution of 0.7–1 mm up to 5-cm depth. In most of the cases, frequencies of 10–14 MHz or higher are preferred, and linear transducers with lower frequency are required in selected cases, ensuring depth penetration [23, 24].

High-resolution US is the most widely used evaluation of thyroid nodules, both for screening purposes and in presurgical settings [25–27]. US of the neck currently represents the most affordable, sensitive, and efficient imaging method for evaluating thyroid morphology, and it is widely available; its role in differentiating cancerous nodules from nonmalignant ones is crucial [19, 28–30].

Considering the large accessibility to US equipment, the current trend is to have standardized homogeneous reports, describing the general aspect of the thyroid, its volume, the presence or the absence of nodules, the number of nodules, their size, position, extracapsular relations, and the following US characteristics: internal composition (solid, cystic, or mixed), shape, margins, echogenicity, echotexture, the presence of echogenic foci, and the Doppler vascular pattern [31].

Certain US features [24, 32–35] have been described to be highly specific for malignancy, such as solid or mostly solid composition, the presence of microcalcifications, spiculated margins, markedly hypoechoic texture, extrathyroidal extension, and "taller than wide" shape, namely, the vertical diameter exceeds the transverse one. These findings are established especially for papillary carcinomas [36]. The US characteristics of follicular cancers are highly similar to follicular adenomas, and no typical appearance was described for medullary thyroid cancer (MTC), but some small studies found that half of the studied MTCs were solid, and hypoechoic and microcalcifications were more prevalent (16%) than in the benign controls [37]. Benignity-related features include smooth margins, a spongiform appearance, and completely cystic composition [38]. **Figure 1** displays the images of US low- and high-risk thyroid nodules.

After the comprehensive examination of thyroid morphology, the presence of cervical lymph nodes (LNs), their number, and appearance should be looked for,

#### **Figure 1.**

*B-mode image of a thyroid nodule with (a) low-risk US appearance (oval-shaped, isoechoic, peripheral halo, regular margins), benign nodule and (b) high-risk US appearance (inhomogeneous, hypoechoic, punctate echoic foci, and irregular borders), papillary thyroid cancer.*

particularly in cases with intermediate- and high-risk nodules [9]. Hilum absence does not diagnose malignancy, but its presence removes its suspicion [39]. An enlarged short-axis diameter is predictive of malignancy, but it is not relevant for the long axis [39–42]. When evaluating multinodular goiters, all the lesions should be described, and their appearance should be assessed in all the cases. If more than one nodule presents features of risk, each of them should be further assessed by FNAC [7, 8, 24].

The concept of thyroid imaging reporting and data system (TI-RADS) was introduced by Horvath et al. in 2009 [43]; these quantitative US classifications are currently used for a more accurate stratification of the US risk of malignancy [44–46].

## **3. Elastography in the evaluation of thyroid nodules**

US elastography noninvasively estimates the stiffness of a thyroid nodule by measuring the tissue displacement, respectively, the internal or external mechanic constraint induced to the tissue. The distortion appears when the nodule is compressed

by a controlled external pressure, as in strain imaging, or the shear waves (SWs) induced by the US probe itself—in shear-wave elastography (SWE) [9]. It grants for "virtual palpation" of the thyroid nodules, which otherwise may not be palpable. Stiff nodules are considered to have an increased risk due to the desmoplastic transformation, disclosing firm, and tumor stroma, characterized by abundant myofibroblasts and collagen fibers [47].

Thyroid elastography was recognized starting with the 2016 American Association of Clinical Endocrinology (AACE) guidelines in the diagnosis of thyroid nodules, complementary to grayscale, and importantly, they do recommend that stiff nodules should be further evaluated by FNAC [48]. It is imperative to take into account the recommendations formulated by the 2017 World Federation for Ultrasound in Medicine and Biology (WFUMB) guidelines on the clinical use of ultrasound elastography in thyroid diseases, which validate the use of USE as an additional tool in thyroid evaluation, no matter the technique [24]. Thyroid elastography was also employed for diffuse diseases, including autoimmune thyroid disease, aiming to assess the severity of fibrosis [49]. As for multinodular goiter, elastography should be used to assess the firmness of each nodule within the thyroid, when the technique is available to the examiner [7, 24]. Together with color Doppler evaluation, it can be of help, when aiming to distinguish between one heterogeneous nodule and the aspect of multiple overlaid lesions appearing as one.

Currently available elastography techniques have various limitations related to the shear properties of the tissue. Nonetheless, in some cases, they may be complementing each other [20]. Elastography can be easily used in the assessment of the thyroid gland taking into account its conveniently superficial position, but it is still not largely embraced in practice, nor comprised in all the risk stratification systems [24].

Still, there are some open questions: Could we upgrade the risk category in nodules with high stiffness, as suggested by the previous mentioned guidelines? Is there a recommended threshold for qualitative measurements suggestive for a special risk category, as seen in breast elastography guidelines, which elastography technique should we use?

#### **3.1 Strain elastography**

Strain elastography (SE) was the first to be used, and it proved to be of great value in thyroid imaging. It displays tissue stiffness, defined as the difference in length along compression divided by the length ahead of compression. Elasticity is expressed as the Young's modulus, the relation between the stress that is applied and strain (E = stress/strain) [20]. The compression can be external, slightly applied manually by the operator and verified by the US machine scale (**Figure 2**); it can be generated by acoustic radiation force impulse (ARFI), or it can be internal, endogenous, by minimal physiologic movement (vascular pulsations and muscle contraction) [20, 50]. The direct quantification of stress is not attainable by the US machines, and strain is displayed relatively through elastograms [51].

#### *3.1.1 Qualitative SE*

The first approach in evaluating strain elastograms (**Figure 3**) is through qualitative pattern-based scoring systems such as the ones described by Asteria et al. [52] on a scale from 1 to 4, with scores 3 and 4 being usually considered suggestive for malignancy and the four-pattern score by Rago et al. [53], where high risk includes scores 4 *Elastography Methods in the Prediction of Malignancy in Thyroid Nodules DOI: http://dx.doi.org/10.5772/intechopen.104261*

#### **Figure 2.**

*Pressure scale (bottom, left) for acquiring optimal elasticity images. Elastogram obtained on a Hitachi Preirus device.*

and 5. The color-map display settings are not currently standardized, and elastograms are carefully interpreted in accordance with the legend on the screen.

Qualitative elastography proved very good diagnostic quality [54, 55]. A metaanalysis that comprised 20 studies assessing the diagnostic value of SE in discriminating cancerous nodules and even its role in reducing FNACs presented a pooled specificity (Sp) of 80%, a sensitivity (Se) of 85%, the positive predictive value (PPV) of 40%, and the negative predictive value (NPV) of 97% [30, 55].

Nevertheless, some authors reported poor inter- and intraobserver agreement for qualitative elastograms [56], but the results were improved for studies using the carotid pulsations (k = 0.79) [57].

#### *3.1.2 Semiquantitative SE*

The strain ratio (SR) (**Figure 4**) provides a numeric value that offers a more objective approach, with less interobserver variability (k = 0.95 [58]) and easier to learn. This semiquantitative parameter is obtained by comparing two manually selected regions of interest (ROIs) within the same captured image, ideally located at the same depth: the first one on the target nodule and the second one on the adjacent reference thyroid parenchyma [59]. Neighboring muscle may be used in cases when thyroid gland is affected by a diffuse disease or there is not enough thyroid tissue found in the image.

SE showed encouraging results in predicting thyroid malignancy, with improved performance over time. A 2013 meta-analysis including 24 studies yielded better diagnostic performance for SE compared to conventional US features (Se = 82% and Sp = 82% for the qualitative score and Se = 89% and Sp = 82% for the strain ratio) [60]. A 2017 meta-analysis reported Se = 84% and Sp = 90% [61]. The cutoff values for the SR in real-time elastography vary in different studies and with the equipment

#### **Figure 3.**

*Qualitative strain elastograms: A—Soft nodule, Asteria 1, benign nodule; B—Mostly stiff nodule, Asteria 3, papillary carcinoma (Hitachi Preirus equipment—The color blue displays hard tissue).*

that was used: SR > 4 with 96% specificity and 82% sensitivity [62]; SR >2.7 with 93.6% accuracy [63]; SR > 2 with 93.8% accuracy [64]; SR > 2.45 with 73.9% sensitivity and 73% specificity; and SR > 4 with 95% accuracy [65].

#### *3.1.3 2B us + SE*

An approach combining conventional US and elastography was proposed. Initially, results were conflicting. Moon et al. found no significant improvement in diagnosis when combining the two imaging methods [66]. However, other studies found excellent results when adding SE to the standard US evaluation. Trimboli et al. reported for the combined assessment Se = 97% and NPV = 97% versus US-only Se = 85% and NPV = 91% [67]. Russ et al. presented a TI-RADS classification including SE parameter "stiffness" in the risk-assessment strategy, obtaining increased sensitivity (96.7% vs. 92.5%), but decreased specificity [68].

The role of strain elastography was assessed for the category of micronodules (less than 10-mm diameter). A small study including 86 patients demonstrated the value of the technique in detecting microcarcinomas with good diagnostic value in area under the receiver operating characteristic (AUROC): 0.743, with the sensitivity (Se) of 88.9% and the specificity (Sp) of 89.3%. In addition, the missed diagnosis rate was significantly lower for SE compared to conventional ultrasound (p < 0.05) [3].

*Elastography Methods in the Prediction of Malignancy in Thyroid Nodules DOI: http://dx.doi.org/10.5772/intechopen.104261*

#### **Figure 4.**

*Strain ratio—Nodule-to-parenchyma—Is 0.95. Soft nodule, similar strain as reference neighboring thyroid tissue; benign micronodule.*

Some of the drawbacks of the technique consist in its subjectivity and its dependency on the operator and on compressibility [61]. Some authors outlined an altered performance for nodules bigger than 3 cm, as well as for very small ones, and for coalescent nodules [22, 24, 69].

Increased stiffness can be identified in benign nodules with fibrosis or coarse calcification, generating false-positive results [70, 71]. **Figure 5** illustrates an artifact generated by intranodular calcification that may falsely indicate a stiff thyroid nodule.

**Figure 5.** *SE false-positive result: Intranodular calcification in the ROI.*

Presently, it is well established that follicular carcinomas may appear misleadingly elastic in SE; therefore, elastography may not be appropriate for diagnosing this particular category (44% false-negative results); other nonpapillary cancers or metastasis may also be soft [24, 70].
