Reviewing secondary outcomes of the ElaTION trial for thyroid nodules

The article entitled ‘Diagnostic Performance of Ultrasound vs. Ultrasound-Guided FNAC in Thyroid Nodules: Data From the ElaTION Trial’ by Mehanna et al. published in 2025, serves as the focus of this editorial commentary (1). Before exploring the article’s merits, we wish to outline the current challenges in managing thyroid nodules, as well as the relevant ultrasound (US) and cytopathological classification systems used in their diagnostic evaluation. This background information is essential for gaining a clearer understanding of the research and its broader context.

Thyroid nodules are common in the general population (2,3). With a female-to-male ratio of 4:1, and an increasing prevalence with older age, it affects 30% to 40% of individuals aged ≥50 years (4-7). Most nodules are asymptomatic and incidentally discovered on imaging performed for other clinical indications. In general, incidentally detected thyroid nodules are seen in up to 68% of cases on US and 15% on computed tomography or magnetic resonance imaging (8-12). The prevalence of thyroid nodules has risen in recent decades (13-15). This is attributed to greater imaging volumes per capita, which have led to higher detection rates of small, clinically silent thyroid nodules. Up to 90% of thyroid nodules are benign, while 10% are malignant (16,17). Among thyroid cancers, papillary cancer constitutes 80% to 85% of total cases, with most of these cancers being slow-growing and exhibiting indolent biologic behavior. These small, localized thyroid cancers rarely lead to death, particularly in older patients, where mortality is frequently due to other comorbidities. The increased detection of thyroid nodules on imaging has led to more surgical interventions. However, the data indicate that treating these cancers does not confer an additional survival advantage, and the mortality has remained stable compared to previous decades (7,8). Overall, this trend towards overdiagnosis and overtreatment of predominantly small clinically silent thyroid cancers represents a socioeconomic burden for healthcare systems globally. In the United States, overdiagnosis of thyroid cancers occurs in 70–80% of females and 45% of males (8,14). In the United Kingdom, the diagnostic workup of thyroid nodules is estimated to cost the National Health Service over £272 million per year (1).

Given the high prevalence of thyroid nodules and to prevent indiscriminate biopsies, various US-based classification systems have been developed to risk-stratify nodules and determine which can be safely ignored, which can be managed conservatively with imaging follow-up, and which require further investigation with biopsy (3). The most well-known of these US-based classification systems is the American College of Radiology Thyroid Imaging Reporting and Data System (ACR TI-RADS), introduced in 2017 (8). In this system, nodules are assigned a points score based on a combination of US findings, including composition, echogenicity, shape, margins and echogenic foci. The overall score is risk-stratified into 1 of 5 TR levels: TR1 ‘benign’ (0 points), TR2 ‘not suspicious’ (2 points), TR3 ‘mildly suspicious’ (3 points), TR4 ‘moderately suspicious’ (4–6 points), and TR5 ‘highly suspicious’ (≥7 points). The TR level is then evaluated alongside nodule size to generate recommendations. Fine-needle aspiration (FNA) biopsy is indicated for TR3 to TR5 nodules, depending on the size threshold. FNA is recommended for TR3 nodules ≥2.5 cm, TR4 nodules ≥1.5 cm, and TR5 nodules ≥1 cm. Additionally, it should be noted that other US-based classification systems, including European Thyroid Imaging and Reporting Data System (EU-TIRADS) and Korean Society of Thyroid Radiology Thyroid Imaging Reporting and Data System (K-TIRADS), have also achieved good diagnostic performance for thyroid nodule assessment, and are effective screening methods for thyroid cancer (18-20).

In the United Kingdom, the ultrasound ‘U’ classification, endorsed by the British Thyroid Association, has been in use since 2014 (Table 1) (21,22). Findings corresponding to U1 and U2 are considered reassuring, while FNA biopsy is recommended for all U3–U5 nodules, regardless of size. In a study of 308 thyroid nodules in 296 patients, McClean et al. showed that the ‘U’ classification had a higher sensitivity (88.1% vs. 73.3%, P=0.0002) but lower specificity (41.6% vs. 64.2%, P<0.0001) compared to ACR TI-RADS for detecting malignant nodules, using histopathology as the reference standard (23). Furthermore, the data indicated that the positive predictive values for both US classifications were comparable when evaluating nodules of equivalent risk scores: U3 vs. TR3 (P=0.81), U4 vs. TR4 (P=0.30), U5 vs. TR5 (P=0.90) (23).

Thyroid cytopathology is reported using the Bethesda System (3rd edition, 2023) in the United States and the Thy System in the United Kingdom (Table 2) (21,24). Bethesda categories I and II correspond to Thy 1 and 2, respectively. Likewise, Bethesda category III corresponds to Thy 3a, Bethesda category IV to Thy 3f, Bethesda category V to Thy 4, and Bethesda category VI to Thy 5.

The ElaTION trial, conducted by Mehanna et al., was a multicenter, unblinded, randomized controlled trial conducted across 18 secondary and tertiary hospitals in England from February 2015 to September 2018. The primary analysis, published in Radiology in 2024, indicated that elastography US-guided fine-needle aspiration cytology (FNAC) did not provide an additional benefit over standard US-guided FNAC in differentiation between benign vs. malignant thyroid nodules (25). The secondary trial outcomes, discussed in this commentary, were published a year later in the Journal of Clinical Endocrinology & Metabolism (1). This study aimed to assess the accuracy of US vs. US-guided FNAC in diagnosing thyroid nodules. The eligibility criteria included euthyroid individuals aged 18 years or older with single or multiple nodules. Exclusion criteria included a US-guided FNAC in the previous 6 months, pregnancy, bleeding diathesis, needle phobia that prevented FNA, and US evidence of recent hemorrhage within a thyroid nodule. During the trial, operators—either consultant radiologists or senior sonographers who had completed a 5-step training accreditation developed by ElaTION—had access to the complete clinical information of participants. In cases with multiple nodules, the most suspicious nodule on US was analyzed. All aspects of patient management, including the selection of nodules to biopsy and who received surgery, adhered to British Thyroid Association guidelines. Participants were discharged from the trial after reaching a final definitive diagnosis (FDD), which was determined by: (I) definitive post-surgical histology; (II) two benign Thy 2 results; (III) a combination of one U2 finding and one Thy 2 result; (IV) a 1-year follow-up if a definitive diagnosis was not achieved within the first year. A malignant FDD was based on receiving a malignant diagnosis on histology. A benign FDD was based on any of the following: a benign diagnosis on histology, two Thy 2 results, or the combination of one U2 finding and one Thy 2 result.

Of the 982 participants enrolled in the trial, a final diagnosis was obtained in 688, who were included in the final analysis. The mean age was 51.3±15.2 years, and 80.3% were female. A multinodular thyroid was identified in 71% of cases. 79% of nodules were ≤4 cm, with a mean size of 2.74±1.56 cm. 53% of nodules were solid, and 47% were solid-cystic. Nodules were isoechoic in 55%, hypoechoic in 36%, and hyperechoic in 9%. Both trial arms were well-balanced with respect to baseline characteristics. On US assessment, U2 findings were seen in 29.5%, U3 in 54.2%, U4 in 11.5%, and U5 in 4.3%. In participants with an FDD, a benign diagnosis was demonstrated in 78% and a malignant diagnosis in 22%. For malignant nodules, outcome analysis showed no significant difference in sensitivity between US (0.91, 95% CI: 0.85 to 0.97) vs. US-FNAC (0.87, 95% CI: 0.80 to 0.95; P=0.37). However, the specificity for benign nodules was lower with US (0.48, 95% CI: 0.40 to 0.52) than with US-FNAC (0.67, 95% CI: 0.61 to 0.73; P<0.0001). The risk of malignancy increased with higher ‘U’ classification grading (U2, 3.4%; U3, 22.4%; U4, 51.8%; U5, 76.3%; P<0.0001). The malignancy rate for nodules classified as benign on cytology (Thy 2) was 4.25%. Furthermore, the malignancy risk for nodules classified as benign on both US and cytology (U2Thy2) was 1.43%. Thy 3 and Thy 3f nodules carried the same malignancy risk (28.4% vs. 37.2%, P=0.18). Malignancy rates appeared to be higher in small nodules: 38.3% in nodules <1 cm vs. 28.4% in nodules between 1 and 2 cm vs. 17.2% in nodules >2 cm (P<0.0001).

The study has several strengths. It is a large, prospective, multicenter trial with a pragmatic, real-world design and strong participation from both secondary and tertiary hospitals. It delivers high-quality, evidence-based data and was conducted in accordance with the Standards for Reporting Diagnostic Accuracy Studies (STARD) guidelines. Historically, the guidelines for managing thyroid nodules established by the British Thyroid Association (2014) and the American Thyroid Association (2015) have heavily relied on retrospective single-institution studies performed at expert centers (21,26). This trial directly compares the diagnostic performance of US vs. US-FNAC for evaluating thyroid nodules. This important clinical question is addressed in one of the largest prospective studies available in the medical literature. In contrast, most previous studies compared the US with histology. This trial confirms the effectiveness of US in evaluating thyroid nodules, in support of recent guidelines, and validates the ‘U’ classification system (21,26). It provides detailed risk estimates for combined US-cytology strata, offering specific malignancy rates for various US-Thy combinations rather than merely presenting area under the curve (AUC) values. This information enhances shared decision-making and complements existing ACR-TI-RADS category-based risk estimates (3,27). The trial findings have implications for future strategy, including highlighting a need for caution regarding current guideline recommendations on the conservative management of non-diagnostic (Thy 1/Bethesda I) and atypical (Thy 3/Bethesda III) nodules. When accompanied by U3–U5 findings, these nodules constitute a high-risk subgroup that warrants more proactive management.

The trial has several limitations. An incomplete FDD was present in 294 of 982 (30%) participants. The fact that only 70% of participants had a complete FDD may introduce verification bias, as clinicians may have preferentially evaluated nodules they were more concerned about. Additionally, the trial was not formally powered to assess differences in thyroid cancer accuracy between US vs. US-guided FNAC. Small strata such as U2Thy3f and U5Thy1 contain few cases and wide confidence intervals. The reported malignancy rates for Thy 1 (12.1%) and Thy 3a (28.4%) are likely upper-bound estimates—the authors acknowledge this selection bias, but the numbers are heavily used in the study’s interpretation. Furthermore, the trial employed a composite reference standard with a minimum follow-up period of 1 year. While this approach may exclude aggressive malignancies, it could potentially miss some low-risk cancers. The lack of blinding between the US interpretation and FNAC/clinical management could lead to review and incorporation bias, particularly affecting which participants receive surgical intervention and, consequently, histological confirmation. Given the use of ‘U’ and Thy classifications in the trial methodology, the trial finding may have limited generalizability outside the United Kingdom, where this system of practice is not used. Molecular testing and AI-based risk tools were not integrated into the trial design. While this exclusion may have been intended to keep the trial design ‘clean’, it limits the trial’s applicability when looking at innovative solutions that may advance thyroid nodule management.

The trial findings raise some questions. The prevalence of malignancy was unexpectedly high at 22%, exceeding the 10% rate commonly cited in the medical literature (16,17). No explanation was provided for this discrepancy. The literature presents conflicting reports regarding the relationship between thyroid nodule size and cancer risk. The trial findings indicated a higher malignancy rate in small nodules (38.3% in nodules <1 cm vs. 17.2% in nodules >2 cm). However, an exploratory post hoc analysis (results not reported in the study) suggested that nodule size was not a significant predictor of cancer. The authors offer a potential explanation for this finding, pointing to radiologist selection bias: a reluctance to biopsy smaller nodules unless they exhibit US findings strongly suggesting malignancy, whereas adopting a lower threshold for biopsy of larger nodules with less suspicious features.

In conclusion, the trial by Mehanna et al. confirms that US-based risk stratification alone can achieve sensitivities comparable to those of FNAC-based pathways. This reinforces the direction of thyroid nodule management guidelines established by the British Thyroid Association (2014) and American Thyroid Association (2015). It aligns with large meta-analyses that show that US-based systems, such as ACR-TI-RADS, can safely reduce the number of unnecessary FNAs while maintaining high sensitivity (27,28). Furthermore, it supports reviews highlighting that US features are highly informative in indeterminate cytology (Bethesda III to IV/Thy 3a and 3f) and can re-stratify risk (3,29). Finally, it contributes prospective multicenter real-world evidence to the literature that is currently dominated by retrospective single-center studies.

Acknowledgments

None.

Footnote

Provenance and Peer Review: This article was commissioned by the editorial office, Gland Surgery. The article has undergone external peer review.

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-1-589/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-1-589/coif). The authors have no conflicts of interest to declare.

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