European Journal of Cardiovascular Medicine

Thyroid nodules are a highly prevalent endocrine disorder, detected in up to 68% of the adult population via high-resolution ultrasonography [1]. While the vast majority of these nodules are benign, approximately 5-15% are malignant, necessitating accurate risk stratification to guide clinical management and avoid both missed cancers and unnecessary interventions [2].

Conventional B-mode ultrasonography (US) is the cornerstone of initial thyroid nodule evaluation. It assesses various morphological features, including composition, echogenicity, shape, margins, and the presence of calcifications. To standardize reporting and reduce inter-observer variability, several risk stratification systems have been developed, most notably the American College of Radiology (ACR) Thyroid Imaging, Reporting, and Data System (TI-RADS) [3]. While TI-RADS has demonstrated high sensitivity for detecting malignancy, its specificity can be suboptimal, particularly for nodules in the intermediate suspicion categories (TI-RADS 3 and 4), leading to a significant number of fine-needle aspiration (FNA) biopsies performed on benign nodules [4].

In recent years, advanced ultrasound techniques have emerged to improve diagnostic accuracy. Ultrasonographic elastography is a non-invasive imaging method that provides an estimation of tissue stiffness. The underlying principle is that malignant tissues, due to increased cellularity, fibrosis, and disorganized architecture, are typically harder and less deformable than benign tissues [5]. Strain elastography (SE), one of the main elastographic techniques, is a qualitative or semi-quantitative method that assesses tissue deformation in response to an externally applied or internal physiological compression. The resulting strain is color-coded and superimposed on the B-mode image, with stiffer areas typically displayed in blue and softer areas in red/green [6]. This can be evaluated qualitatively using an elastography score (ES) or semi-quantitatively by calculating a strain ratio (SR) between the nodule and adjacent normal thyroid parenchyma.

Several studies and meta-analyses have demonstrated the utility of SE in thyroid nodule assessment, reporting that it can significantly improve the specificity and overall accuracy of conventional US [7, 8]. However, there remains ongoing discussion regarding the optimal diagnostic criteria, the relative value of qualitative versus quantitative assessment, and the ideal way to integrate SE findings with established systems like TI-RADS. Some studies have shown variable performance, potentially due to operator dependency, differences in equipment, and challenges with certain nodule types, such as those with cystic components or extensive calcifications [9].

This study was designed to address this gap by prospectively evaluating the diagnostic performance of both qualitative (ES) and quantitative (SR) strain elastography in a cohort of patients with histopathologically confirmed thyroid nodules. The primary aim was to determine if the addition of SE to conventional B-mode US assessment improves the diagnostic accuracy for differentiating benign from malignant thyroid nodules.

Study Design and Population: This was a prospective, single-center, diagnostic accuracy study conducted at the Department of Radiology of University Hospital from January 2023 to June 2024

The study population consisted of consecutive adult patients (≥18 years) referred for ultrasound-guided FNA or scheduled for thyroid surgery for one or more thyroid nodules.

Inclusion Criteria:

1. Presence of at least one solid or predominantly solid thyroid nodule measuring ≥10 mm in its largest diameter.
2. Nodule classified as TI-RADS 3 or higher, warranting cytological or histological evaluation.
3. Availability of a definitive final diagnosis from either FNA cytology (Bethesda V or VI for malignant; Bethesda II for benign) or post-surgical histopathology.

Exclusion Criteria:

1. Purely cystic nodules.
2. Nodules with coarse macrocalcifications or eggshell calcifications causing significant acoustic shadowing that precluded proper elastographic assessment.
3. Patients with a history of neck irradiation or previous thyroid surgery.
4. Inadequate quality of the elastography examination (e.g., due to patient movement or poor compression technique).

A total of 148 patients with 162 nodules met the inclusion criteria and were enrolled in the study.

Ultrasound and Elastography Protocol: All examinations were performed by one of two radiologists, each with over 10 years of experience in thyroid imaging, using a high-resolution ultrasound system (Hitachi Ascendus, Hitachi Medical Systems, Tokyo, Japan) equipped with a 5–18 MHz linear-array transducer. The radiologists were blinded to the final histopathological results at the time of imaging.

B-mode Ultrasound Examination: Each nodule was systematically evaluated for its size (maximum diameter), composition (solid, predominantly solid, mixed), echogenicity (hyperechoic, isoechoic, hypoechoic, very hypoechoic), shape (taller-than-wide vs. wider-than-tall), margins (well-defined, ill-defined, lobulated, or irregular), and the presence of echogenic foci (macrocalcifications, microcalcifications, etc.). Based on these features, a final TI-RADS category was assigned according to the ACR TI-RADS guidelines. Nodules classified as TI-RADS 4 or 5 were considered suspicious for malignancy on B-mode US.

Strain Elastography Examination: Immediately following the B-mode assessment, SE was performed. The transducer was positioned lightly over the nodule, and gentle, rhythmic vertical compression was manually applied. A quality indicator on the system was used to ensure optimal and consistent compression amplitude.

1. Qualitative Assessment (Elastography Score - ES): The stiffness of the nodule was scored using the 4-point elasticity scoring system proposed by Itoh et al. The scores were assigned as follows: Score 1, entire nodule is evenly soft (green); Score 2, nodule is mostly soft with some hard areas (mosaic green/blue); Score 3, nodule is predominantly hard (blue); Score 4, entire nodule is hard (blue), with or without extension to surrounding tissue. For analysis, scores of 3 and 4 were considered indicative of malignancy.
2. Quantitative Assessment (Strain Ratio - SR): A semi-quantitative analysis was performed by placing two regions of interest (ROIs). The target ROI was placed over the stiffest portion of the nodule, avoiding cystic or calcified areas. A reference ROI of the same size was placed over adjacent, normal-appearing thyroid parenchyma at the same depth. The system automatically calculated the SR as the ratio of strain in the reference tissue to the strain in the target nodule. The mean of three SR measurements was recorded for each nodule.

Reference Standard: The final diagnosis for each nodule was obtained from histopathology. For nodules undergoing surgery, the post-operative histopathology report was the gold standard. For nodules evaluated by FNA only, a result of Bethesda category II (Benign) was accepted as benign, while Bethesda categories V (Suspicious for Malignancy) and VI (Malignant) were considered malignant. Nodules with indeterminate cytology (Bethesda I, III, IV) were only included if a final surgical histopathology was available.

Statistical Analysis: All statistical analyses were performed using SPSS for Windows, version 26.0 (IBM Corp., Armonk, NY). Continuous variables were expressed as mean ± standard deviation (SD) and compared using the independent samples t-test. Categorical variables were expressed as numbers and percentages (%) and compared using the Chi-square test or Fisher’s exact test, as appropriate.

Receiver operating characteristic (ROC) curve analysis was conducted to determine the optimal cutoff values for ES and SR that maximized the Youden index (sensitivity + specificity - 1). The area under the curve (AUC) was calculated to assess the overall diagnostic ability. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were calculated for B-mode US (TI-RADS), SE (ES and SR), and the combined assessment. A p-value of <0.05 was considered statistically significant.

Patient and Nodule Characteristics: A total of 162 nodules from 148 patients (118 female, 30 male; mean age 51.2 ± 13.5 years) were included in the final analysis. Histopathological analysis confirmed 125 (77.2%) benign nodules and 37 (22.8%) malignant nodules.

The malignant group comprised 29 papillary thyroid carcinomas, 5 follicular thyroid carcinomas, 2 medullary thyroid carcinomas, and 1 anaplastic carcinoma. The demographic and B-mode US characteristics of the benign and malignant nodules are summarized in Table 1. Malignant nodules were significantly more likely to be classified as TI-RADS 4 or 5 (p < 0.001). There was no significant difference in mean nodule size or patient age between the two groups.

Table 1. Demographic and B-mode Ultrasound Characteristics of Benign and Malignant Nodules

Data are presented as mean ± SD or n (%). p-values calculated using independent t-test or Chi-square test.

Strain Elastography Findings: Both qualitative and quantitative SE parameters showed significant differences between benign and malignant nodules (Table 2). The mean ES for malignant nodules was significantly higher than for benign nodules (3.5 ± 0.7 vs. 1.9 ± 0.8, p < 0.001). Similarly, the mean SR was significantly higher in the malignant group (4.8 ± 1.4 vs. 2.1 ± 0.9, p < 0.001).

Table 2. Comparison of Strain Elastography Parameters between Benign and Malignant Nodules

Diagnostic Performance Analysis: ROC curve analysis for SR yielded an AUC of 0.93 (95% CI: 0.88–0.98), with an optimal cutoff value of 2.95 providing a sensitivity of 89.2% and a specificity of 89.6%. For ES (using a cutoff of ≥3), the AUC was 0.88 (95% CI: 0.82–0.95).

The diagnostic performance of B-mode US (TI-RADS ≥4 as malignant), SE (SR > 2.95 as malignant), and a combined approach (positive if TI-RADS ≥4 AND SR > 2.95) are detailed in Table 3. The combined approach demonstrated the highest overall accuracy (92.0%), which was significantly better than B-mode US alone (84.0%, p = 0.02). The combination also yielded the highest specificity (91.2%) and NPV (98.3%).

Table 3. Diagnostic Performance of B-mode US, Strain Elastography, and Combined Assessment

SE: Strain Elastography; SR: Strain Ratio; PPV: Positive Predictive Value; NPV: Negative Predictive Value; AUC: Area Under the ROC Curve.

The accurate differentiation of benign and malignant thyroid nodules remains a significant clinical challenge. This study prospectively evaluated the utility of strain elastography as an adjunct to conventional B-mode US and found that its integration significantly improves diagnostic performance. Our primary finding is that malignant nodules are substantially stiffer than benign nodules, as demonstrated by significantly higher qualitative elastography scores and quantitative strain ratios.

The results of our study are consistent with the growing body of literature supporting the role of elastography in thyroid nodule assessment. A large meta-analysis by Sun et al. reported a pooled sensitivity and specificity of 84% and 88%, respectively, for strain elastography, which aligns closely with the performance of SR in our cohort [8]. We found that the quantitative SR (AUC = 0.93) offered slightly better diagnostic discrimination than the qualitative ES (AUC = 0.88), suggesting that a semi-quantitative approach may be more objective and reproducible. The optimal SR cutoff of 2.95 identified in our study is also within the range of 2.5 to 4.0 reported by most previous investigations [7, 10].

The most important clinical finding of this study is the enhanced accuracy achieved by combining B-mode US features (via TI-RADS) with SE data. While TI-RADS alone offered high sensitivity (91.9%), its specificity was limited (80.0%), which could lead to a high false-positive rate and consequently, a large number of unnecessary FNAs for benign nodules. By adding the SR criterion, we were able to increase the specificity to 91.2% and the overall accuracy to 92.0% while maintaining high sensitivity. This improvement in specificity is crucial. For instance, in our cohort, 25 nodules that were classified as suspicious on B-mode US (TI-RADS 4 or 5) were correctly re-categorized as likely benign based on their low stiffness (SR ≤ 2.95), potentially avoiding an invasive procedure. This highlights the potential of SE to act as a valuable "rule-out" test for malignancy in nodules with indeterminate sonographic features, a role also suggested by Trimboli et al. [11].

Despite the promising results, this study has several limitations that should be acknowledged. First, it was a single-center study with a relatively limited sample size, which may affect the generalizability of our findings. A larger, multi-center trial would be needed to validate our results and SR cutoff value. Second, strain elastography is known to be an operator-dependent technique. Although our examinations were performed by experienced radiologists, variability in applying compression can influence the results. Third, we excluded nodules with extensive calcifications, which are a known limitation for all ultrasound-based elastography techniques [12,13]. The performance of SE in this specific subgroup of nodules requires further investigation. Finally, our reference standard for some benign nodules was a benign FNA result (Bethesda II), which, while highly reliable, carries a very small false-negative rate compared to surgical histopathology.

Future research should focus on standardizing SE techniques to minimize operator variability and on comparing the performance of strain elastography with other techniques like shear wave elastography (SWE), which provides a more quantitative, operator-independent measure of stiffness [14,15]. Furthermore, integrating elastography data into artificial intelligence and machine learning algorithms could further enhance the objectivity and accuracy of thyroid nodule risk stratification.

In conclusion, this study confirms that both qualitative and quantitative strain elastography are effective tools for differentiating benign from malignant thyroid nodules. Malignant nodules are significantly stiffer than their benign counterparts. The addition of quantitative strain ratio measurement to conventional B-mode ultrasonography significantly improves diagnostic specificity and overall accuracy, surpassing the performance of either modality alone. The thoughtful integration of strain elastography into the clinical workflow for thyroid nodule evaluation holds considerable promise for refining risk stratification, thereby reducing the number of unnecessary fine-needle aspirations and improving patient management.

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