International Expert Consensus on US Lexicon for Thyroid Nodules

Round 1 (September to November 2021)

An online survey tool (SurveyMonkey, Momentive) was used to present proposed definitions for seven categories and 25 descriptors. The respondents were provided with digital copies of references selected by the subgroups, along with anonymized comments from subgroup members. Voters rated each definition on a five-point scale: strongly agree, agree, neutral, disagree, or strongly disagree. They were also free to enter optional anonymous comments. Consensus was considered to have been achieved if 80% or more of the voters indicated they agreed or strongly agreed with a definition. Of the 25 descriptors, 20 met the consensus threshold during this round, with five at 100%, two at 95%, six at 90%, and seven at 84%. Five definitions, with scores ranging from 58% to 79%, failed to attain consensus (Table 2).

Table 2: Voting Results and Risk of Malignancy for All I-TIRADS Categories

Round 2 (February 2022)

Next, the round 1 survey results and anonymous comments were sent to all the subgroups. Subgroup leaders were asked to concentrate on the five descriptors that remained below the consensus threshold and suggest edits. The original and alternative definitions were presented in a second voting round in which physicians rated the new definitions using the same scale as before, this time without comments. As previously, 80% agreement, or strong agreement, indicated consensus. The subgroups were also permitted to propose alternate definitions for seven descriptors on which consensus had been reached in round 1. For the latter items, voters indicated whether they preferred the prior or new definition, with a simple majority required for consensus. In round 2, one of the five descriptors attained consensus, leaving four that did not.

Round 3 (March 2022)

The four descriptors were subjected to further deliberation with use of a password-protected online bulletin board (ProBoards, VerticalScope). A separate discussion thread was created for each descriptor, which allowed participants to nonanonymously propose changes and enter comments at their discretion. This method was used in lieu of conference calls because it allowed for asynchronous conversation, which facilitated discourse among participants in widely separated time zones. Consensus was reached on all four.

The Lexicon

Table 2 shows the results of voting for the definitions of the seven categories and their respective descriptors in the I-TIRADS lexicon for thyroid nodules, as well as the estimated risk of malignancy for each descriptor, where available. Figures 2–8 present the definition of each category, followed by definitions and illustrative sonograms for its descriptors. Tables 3 and 4 list the studies cited, along with the study type, number of patients, and reference standard.

Figure 2:

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Figure 3:

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Figure 4:

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Figure 5:

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Figure 6:

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Figure 7:

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Figure 8:

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Table 3: Retrospective Studies Cited for I-TIRADS Descriptors

Table 4: Studies Other than Retrospective Cited for I-TIRADS Descriptors

Composition

Composition (Fig 2) is defined as the proportion of the solid and fluid components in a nodule. Solid composition is associated with malignancy of thyroid nodules (16–19), with a reported sensitivity of 72.7%–87.0% and a specificity of 53.2%–56.0% (16,19). The malignancy risk of purely solid nodules is substantially higher than that of minimally cystic (cystic component <10%) or partially cystic (cystic component >10%) nodules. A Korean study showed that the malignancy risks of minimally cystic and partially cystic nodules (8.8% and 6.2%, respectively) were significantly lower (<10% risk) than the risk for purely solid nodules (29.5% risk) (20). Because estimation of the proportion of the fluid component in mixed nodules may not be accurate, causing low interobserver agreement, the panel chose to define as solid those nodules without any obvious anechoic cystic portions and the others as mixed.

The descriptors predominantly solid and predominantly cystic refer to the relative proportion of each component, with the understanding that this determination is often subjective, particularly if the amounts are nearly equal. Pure cyst refers to nodules that contain only fluid, or fluid with only minimal solid components. This, too, is sometimes a subjective determination, but in practice, it is almost never pivotal in classifying a nodule.

When a spongiform nodule is defined as a nodule having a sponge-like appearance involving nearly the entire nodule volume, the risk of cancer is less than 1% (21). The cystic spaces in spongiform nodules are usually small, but there is overlap with predominantly cystic nodules that contain larger fluid components. Hypoechoic nodules with a partially spongiform appearance have a higher malignancy risk than those that are completely spongiform (22).

The working group elected not to include Doppler US specifically for risk assessment of thyroid nodules because of its variable value in their experience and in the literature. However, Doppler US may be helpful to distinguish viable tissue from necrotic debris, as only the former will exhibit flow. Additionally, as described later, color Doppler US is incorporated into the assessment of cervical lymph nodes.

Echogenicity

Echogenicity (Fig 3) refers to the reflectivity of the noncalcified solid components of a nodule when compared with reference structures. If a nodule is more echogenic than the adjacent thyroid, it is called hyperechoic; if it is equally echogenic, it is isoechoic. Nodules that are less reflective than the thyroid are classified as hypoechoic, with a reported sensitivity of 62.7%–73.0% and specificity of 56.0%–62.3% for malignancy (16,19). Hypoechogenicity may be further subclassified as mild, moderate, or marked, as this further influences the risk of malignancy (16–19). For example, in a recent retrospective study (n = 2255), the malignancy risk of markedly (52.5%) and moderately hypoechoic (58.6%) nodules was significantly higher than that of mildly hypoechoic nodules (19.9%) (23). However, given their similar malignancy risk, the panel elected to combine moderate and marked echogenicity. In the lexicon, mildly hypoechoic is defined as decreased echogenicity relative to the normal thyroid parenchyma but still higher than that of the anterior neck muscles, while markedly hypoechoic is echogenicity less than or equal to that of the anterior neck muscles. The final descriptor in this category, anechoic, is reserved for nodules with no internal echoes such as pure cysts, as defined previously.

A solid nodule may be homogeneous (characterized by uniform echogenicity) or heterogeneous (characterized by variable echogenicity, such as, for instance, in the presence of both hypo- and isoechoic areas). If a nodule exhibits heterogeneous echogenicity, the predominant component determines the echogenicity of the nodule. When the echogenicity of thyroid tissue surrounding a nodule is decreased, as in Hashimoto thyroiditis, the echogenicity of the solid component of the nodule may be assessed relative to normal parenchyma in other parts of the gland, if present. Quantitative estimations (eg, gray-scale analysis or other radiomics techniques) of the degree of echogenicity may be useful to improve interobserver variability; an increase from fair to substantial agreement has been reported (24,25), but they are not widely available. Although the submandibular glands have been proposed as an alternative reference standard, a recent study reported that normal submandibular glands showed decreased echogenicity in more than a quarter of the adult patients (27.0%), rendering them inadequate for this purpose (26).

Margin

Margin (Fig 4) is defined as the border between the thyroid nodule and surrounding thyroid parenchyma. Nodules that exhibit a sharp margin, without projections into the adjacent tissue, are called smooth. Conversely, an irregular margin is associated with an increased risk of malignancy (16–19), with a reported sensitivity of 50.5% and specificity of 83.1% (19). The term irregular encompasses small rounded projections (microlobulated) and jagged, spike-like (spiculated) margins. These were combined in a single descriptor to improve interobserver agreement, which is reported to be slight to fair for this feature, especially when using more subtypes (24,27–29). While some studies report that an ill-defined (poorly discernable) margin has an increased likelihood of malignancy (30–32), the strength of this association is lower when compared with microlobulation or spiculation (32).

Direction of Growth

This refers to the direction of growth of a nodule (Fig 5) relative to the thyroid gland as assessed by the ratio of its linear dimensions. The descriptors in this category are wider-than-tall (parallel) and taller-than-wide (nonparallel), with the latter showing a sensitivity of 26.7%–53.0% and specificity of 93.0%–96.6% for malignancy (16,19). Although some panelists favored evaluating this attribute on either transverse or sagittal images, the former was adopted because the diagnostic performance in both planes is similar and the transverse plane was believed to be easier to understand (33).

Technically, nodules with identical anteroposterior and transverse measurements, which have a round configuration, are neither wider-than-tall nor taller-than-wide. However, for practical purposes, the former descriptor should be applied to such nodules to avoid overcalling taller-than-wide. To mitigate this risk, some panelists suggested establishing a minimum height-to-width threshold, bolstered by evidence that the likelihood of malignancy increases with increasing anteroposterior-to-transverse diameter (34,35). Again, however, for simplicity, the panel decided not to adopt a specific threshold.

Echogenic Foci/Calcifications

Echogenic foci (Fig 6) are focal regions within or along the periphery of a nodule that are markedly hyperechoic relative to the rest of the nodule and the surrounding normal parenchyma. They may vary in size, shape, and location in a nodule. Punctate echogenic foci/microcalcifications (≤1 mm) have an independent association with malignancy (36,37), with a reported sensitivity of 41.6%–75.7%, specificity of 35.1%–92.4%, and positive predictive value of 16.8%–77.9% (36–39). The malignancy risk of nodules containing them depends on the coexistence of descriptors in other US categories, such as composition and echogenicity (38,39). For example, their risk in solid hypoechoic nodules is substantially higher than in solid iso- or hyperechoic or partially cystic nodules (38–40).

Punctate echogenic foci in papillary thyroid cancers are rarely associated with posterior acoustic shadowing (echo voids deep to calcifications) and occasionally show comet-tail artifacts. Therefore, the presence of such artifacts should not preclude application of this descriptor, with the understanding that they are also commonly seen in benign thyroid nodules and may correspond to other pathologic features such as dense colloid or dystrophic calcification, in addition to psammomatous calcifications (41).

Macrocalcifications (>1 mm) are larger than punctate echogenic foci and may be located within the substance of a nodule or along its periphery. Their configuration varies from rounded or nearly so to curvilinear. When they follow the margin of a nodule in a complete or interrupted fashion, they are called peripheral or rim calcifications. Both types may be associated with dense acoustic shadowing that precludes confident assessment of the echogenicity and composition of a nodule; composition may be assumed to be solid when this occurs (42).

Many studies have reported that macrocalcifications confer an increased risk for cancer, with a reported sensitivity of 9.7%–25.0%, specificity 81.6%–96.1%, and positive predictive value of 13.2%–64.8% for malignancy (36,38,39,43,44). However, it is uncertain if macrocalcifications alone are independently associated with malignancy (36,39).

Several studies (38,43,45) have reported that peripheral (rim) calcifications are associated with malignancy, with reported sensitivities of 1.1%–8.9%, specificities of 96.5%–99.4%, and positive predictive values ranging from 16.7% to 57.7%. However, other studies have reported conflicting results (36,46), and it is unclear if this feature confers an increased risk of cancer.

Echogenic foci with triangular comet-tail artifacts often vary in shape and location within a nodule. They are mostly found in the fluid components of cystic nodules and are reliably predictive of benignity (47–49). Similar foci at the margin of the cystic components of partially cystic nodules also favor benignity; however, they can at times be seen in a cystic papillary carcinoma and are not specific for benign or malignant nodules (48). Echogenic foci with comet-tail artifacts in solid tissue have a relatively high malignancy risk and should not be considered a benign feature (49–52).

Extrathyroidal Extension

ETE (Fig 7) describes the spatial relationship between a nodule and the thyroid capsule and perithyroidal structures. (Although the thyroid lacks a complete fibrous capsule, the term was retained, as it has gained widespread acceptance.) The reported sensitivity is 6.8%–86.4%; specificity, 29.8%–100%; and positive predictive value, 39.2%–100% for malignancy, which reflects the degree of certainty that the nodule is truly invasive (53). At the low end, capsule contact is when the nodule touches the border of the thyroid. The echogenic capsule may be bulged, but it remains sonographically intact. Whether a nodule contacts the anterior versus the posterior capsule is relevant to the decision for or against active surveillance (54). However, this feature alone has a positive predictive value too low to justify changes in management of an already planned surgery (53). Suspicious minor ETE, where the capsule is not visible where a nodule abuts it, represents an indeterminate state.

Gross ETE includes a nodule margin that is indistinct and poorly differentiated from the strap muscles (also known as the infrahyoid muscles), the tracheoesophageal groove, or esophagus or forms an obtuse angle with the trachea. Evidence for the predictive value of sonographically detected gross ETE to the trachea or tracheoesophageal groove is limited. Due to the potential impact and morbidity, the Korean recommendations are included herein as suspicious of gross ETE (8). Of note, these tumors are expected to have at least another high-suspicion feature, such as irregular margin, marked hypoechogenicity, punctate echogenic foci, or taller-than-wide shape. When there is gross ETE along the posterior border of the thyroid, US is likely to underestimate the extent of disease. For better surgical planning, complementary cross-sectional imaging with CT or MRI should be considered.

Lymph Nodes

The I-TIRADS lexicon encompasses descriptive terms for regional (cervical) lymph nodes (Fig 8), which are relevant to tumor staging and may influence the need for biopsy of a thyroid nodule. The European Thyroid Association's scheme for lymph node US classification (55), which categorizes nodes based on shape, internal architecture, and other characteristics, was endorsed by the American Thyroid Association and subsequently validated by multiple studies (56,57). The features associated with the I-TIRADS suspicious lymph node descriptor have a reported sensitivity of 5.0%–87.0% and specificity of 43.0%–100% (55). The panel chose to endorse this stratification as a baseline and update it with evidence from more recent studies (58).

Lymph nodes take on different characteristics in different anatomic compartments of the neck. Levels I–VI have different expectations for node size and shape, and even central versus lateral neck nodes may differ (53). Detection of central compartment lymph nodes in patients with an intact thyroid may be more difficult, as their features are harder to recognize than in patients who have undergone thyroidectomy. The coexistence of chronic lymphocytic thyroiditis also may confound lymph node interpretation (59).

As described in Figure 8, nonsuspicious nodes lack suspicious features and have an ovoid shape and/or a visible hilum, while indeterminate nodes fall into an intermediate category. The vast majority turn out to be benign and resolve spontaneously or remain stable over time (57). The risk of malignancy varies according to the clinical context. The positive predictive value of indeterminate features is expected to change according to the pretest probability. For example, indeterminate lymph nodes identified during a screening sonogram with no suspicious findings in the thyroid are at lower risk than those identified in a patient with papillary thyroid cancer.

Features suspicious for thyroid cancer metastases that were included in this category have a high positive predictive value that is consistently reported in the literature. Microlobulated, poorly defined, or irregular margins may increase the suspicion for metastasis (58–60). However, panelists decided not to include these characteristics in the lexicon based on their expert opinion that determining the margin of a lymph node is highly subjective.