Abstract
Objective:
To evaluate the performance of contrast-enhanced ultrasound in the diagnosis of small, solid, TR3–5 benign and malignant thyroid nodules (≤1 cm).
Methods:
From January 2016 to March 2018, 185 thyroid nodules from 154 patients who underwent contrast enhanced ultrasound (CEUS) and fine-needle aspiration or thyroidectomy in Shanghai General Hospital were included. The χ2 test was used to compare the CEUS characteristics of benign and malignant thyroid nodules, and the CEUS features of malignant nodules assigned scores. The total score of the CEUS features and the scores of the above nodules were evaluated according to the latest 2017 version of the Thyroid Imaging Reporting and Data System (TI-RADS). The diagnostic performance of the two were compared based on the receiver operating characteristic curves generated for benign and malignant thyroid nodules.
Results:
The degree, enhancement patterns, boundary, shape, and homogeneity of enhancement in thyroid small solid nodules were significantly different (p＜0.05). No significant differences were seen between benign and malignant thyroid nodules regarding completeness of enhancement and size of enhanced lesions (p＞0.05). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the TI-RADS classification TR5 in diagnosis of malignant nodules were 90.10%, 55.95%, 74.59%, 72.22%, and 82.46%, respectively (area under the curve [AUC]=0.738; 95% confidence interval[CI], 0.663–0.813). The sensitivity, specificity, accuracy, positive predictive value, and negative predictive value of the total score of CEUS qualitative analysis indicators were 86.13%, 89.29%, 87.57%, 90.63%, and 84.27% respectively (AUC = 0.916; 95% CI, 0.871–0.961).
Conclusion:
CEUS qualitative analysis is superior to TI-RADS in evaluating the diagnostic performance of small, solid thyroid nodules. Qualitative analysis of CEUS has a significantly higher specificity for diagnosis of malignant thyroid nodules than TI-RADS.
Advances in knowledge:
The 2017 version of TI-RADS has recently suggested the malignant stratification of thyroid nodules by ultrasound. In this paper we applied this system and CEUS to evaluate 185 nodules and compare the results with pathological findings to access the diagnostic performance.
Introduction
Conventional ultrasound is the main imaging method for evaluation of the thyroid gland and can detect up to 68% of thyroid nodules of which 1.6–12.0% are malignant.1–3 Papillary thyroid carcinoma (PTC) is the most common malignant thyroid tumour, with a rapidly increasing global incidence in recent years. Papillary thyroid microcarcinoma (PTMC, i.e. the maximum diameter:≤1 cm) accounts for 48.8% of all PTCs in France and 38.5% of all cases in the United States.4,5 As PTMC is generally believed to be inert and non-invasive, it is not necessary to perform fine needle aspiration (FNA).6–8 However, about 37.3% of PTMCs can cause central lymph node metastasis (CLNM).9,10 CLNM is an important factor known to affect the prognosis of thyroid cancer. A previous study suggested that metastatic PTMC needs more aggressive clinical management, such as radioactive iodine treatment and lymphadenectomy for an excellent long-term prognosis.11 Therefore, accurate diagnosis of thyroid nodules with a maximum diameter ≤1 cm is critical for better clinical management and outcome.
The American College of Radiology (ACR) published the latest white paper on the Thyroid Imaging Reporting and Data System (TI-RADS) in 2017. On the basis of conventional ultrasound features, ACR TI-RADS assigns scores to five indicators: composition, echogenicity, shape, margin, and echogenic foci. The sum of these scores corresponds to a risk level, including TR1 (benign), TR2 (not suspicious), TR3 (mildly suspicious), TR4 (moderately suspicious), or TR5 (highly suspicious). It provides a standard system for risk stratification and management for thyroid nodules detected with ultrasound.12,13 According to the classification of ACR TI-RADS, solid thyroid nodules ≤ 1 cm are classified as TR3–5, which indicate low, moderate, high risk of malignancies, respectively. However, ACR TI-RADS does not recommend FNA when the nodule’s maximal diameter is ≤1 cm. Therefore, it is controversial whether ACR TI-RADS can accurately evaluate the diagnostic performance of such nodules and validation by other examination methods is required. Contrast-enhanced ultrasound (CEUS) holds promise.
Conventional ultrasound reveals the morphologic features of a tumour and blood flow information within the region of interest (ROI), but it has low ability to reflect microvascular perfusion information within the ROI. By injection of ultrasound contrast agents, CEUS can detect dynamic vascularity and microvascular perfusion of the tumour, both qualitatively and quantitatively, in a non-invasive manner. By conventional ultrasound, it is difficult to detect bleeding sites and hematomas with abdominal trauma, while CEUS has made it possible to overcome the drawbacks of conventional ultrasound technique by visualisation of the microcirculation.14 The application of CEUS in the liver has been incorporated into the European Federation of Societies for Ultrasound in Medicine and Biology (EFSUMB) guidelines.15Some studies have suggested that CEUS is also valuable in differentiating benign and malignant breast lesions.16,17 Yu et al.18 showed that qualitative analysis of CEUS has higher sensitivity and specificity than quantitative analysis in the differential diagnosis of benign and malignant thyroid nodules. Therefore, the aim of this study was to further evaluate the diagnostic performance of qualitative CEUS analysis for small, solid benign and malignant thyroid TR3-5 nodules (≤1 cm).
Methods
Patients
This retrospective study was approved by the ethics committee of Shanghai General Hospital, and all patients provided written informed consent before undergoing CEUS. This study was carried out over 27 months, from January 2016 to March 2018. A total of 417 nodules in 314 consecutive patients were imaged with conventional ultrasound and CEUS. Of these, 232 nodules in 160 patients were not recruited for the following reasons: (1) complete or partial cystic nodules (number of patients [N]=59 and number of nodules [n]=88); (2) nodules larger than 1 cm (N = 74, n = 99); (3) no definite FNA diagnosis or surgical pathological results (N = 21, n = 36); (4) the maximum diameter of nodules＜0.5 cm (N = 6, n = 9). The inclusion criteria were as follows: (1) all nodules were diagnosed as solid nodules by ultrasound; (2) the maximum diameter of all nodules was ≤1 cm; and (3) all nodules were confirmed by surgical pathology or FNA (Figure 1). 23 patients had a single nodule each, and the remaining 131 patients had multiple nodules.
Figure 1.
The flowchart of patients with thyroid nodules selection. N = number of patients; n = number of thyroid nodules. *Five patients each had one malignant and one benign thyroid nodules.
Conventional ultrasound and CEUS
The IU Elite (Philips Medical Systems, Bothell, WA) diagnostic ultrasound system was adopted for conventional ultrasound and CEUS. L12-5 (frequency range: 5–12 MHz) linear array transducer was used for all the conventional ultrasound examinations, and the L9-3 (frequency range: 3–9 MHz) linear array transducer was used for all the CEUS examinations. The examinations were performed by the radiologist who had 10 years of experience in thyroid ultrasound and 3 years of experience in thyroid CEUS.
Patients were placed in the supine position with head held back, and the examination area was fully exposed. For optimal image quality, patients were instructed to breathe calmly and not swallow during the examination. The probe was applied with adequate couplant to make full contact with the skin to ensure the target thyroid nodule was imaged without signal loss. The image settings including focus, wall filter, gain, and colour gain were constantly adjusted until the best images were obtained.
After conventional ultrasound examination, CEUS was performed by the same investigator. Contrast-specific image mode was initiated and the mechanical index (MI) was set to 0.08. Meanwhile, the single-point focus was set below the thyroid nodule. The aim was to generate almost pure microbubble images and prevent microbubbles from being destroyed in the circulation. The second-generation pure blood pool contrast agent SonoVue (Bracco imaging, Milan, Italy), which comprises phospholipid-stabilised shell microbubbles filled with sulphur gas, was injected intravenously as a bolus at a dose of 2.0–2.4 ml, followed by 5 ml 0.9% sodium chloride solution as a flush. The timer was started at the beginning of contrast-agent injection, and the target nodule was observed consecutively for at least 2 min. During the examination, the patient's posture remained unchanged and swallowing was prohibited.
Image analysis
The images of conventional ultrasound and CEUS were recorded and reviewed retrospectively by two radiologists with more than 5 years’ experience in thyroid ultrasound, who were blinded to the pathological results and clinical data. In case of discrepancy between the two investigators, a final consensus was reached after discussion with another radiologist having 10 years’ experience in thyroid ultrasound.
In conventional ultrasound, each target nodule was evaluated for its size (maximal diameter); echogenicity (hyper-, iso-, or hypoechogenicity, compared with the surrounding thyroid tissue, or marked hypoechogenicity, when a nodule showed lower echogenicity than the surrounding strap muscle); composition (spongiform, mixed cystic, and solid); shape (regular or irregular); margin (well or poorly defined); strong echo focus (large comet-tail artefacts, macrocalcifications, peripheral and punctate echogenic foci); and taller than wide and wider than tall signs.12 According to the 2017 edition of the ACR TI-RADS,12 the target nodules were scored based on the components, echo, shape, edge, and strong echo focus of the nodules, and the TR classification of the nodules was obtained according to the total scores.
Qualitative indicators of CEUS analysis in target thyroid nodules included enhancement intensity (hypo-, iso-, or hyperenhancement compared with surrounding normal thyroid tissue in time to peak enhancement, and no-enhancement, indicating that no microbubbles entered the nodule); patterns of enhancement (centrality, centrifugal, diffuse, partiality, ring); internal homogeneity (homogeneity, heterogeneity); perfusion defect (with, without); boundary (clear, unclear); morphology (regular, irregular); and size (enlargement, invariability, decrease) at enhancement peak. The CEUS characteristics of benign and malignant thyroid nodules with significant differential diagnosis were scored, and the total scores of each thyroid nodule were calculated.
Statistical analysis
SPSS 20.0 software package (SPSS Inc, Chicago, IL) was performed for statistical analysis. Comparative analysis of the qualitative indicators of CEUS between benign and malignant nodules was tested using Pearson’s χ2 test or likelihood ratio χ2 test. Independent-samples Kruskal–Wallis test was used to compare the distribution of conventional ultrasound TI-RADS classification and the total scores of CEUS in benign and malignant thyroid nodules. Receiver operating characteristic (ROC) curve analysis was carried out to estimate the diagnostic performance of conventional ultrasound TI-RADS classification and the total scores of CEUS; the areas under the curve (AUCs) and its 95% confidence interval (CI) were also calculated. p < 0.05 was considered statistically significant.
Results
Pathological results
Finally, 185 nodules in 154 patients were included in this study. Of the 185 nodules, 133 were confirmed by surgical pathology. Of these, 35 (26.32%) were nodular goitres, 7 (5.26%) were Hashimoto nodules, 1 (0.75%) was subacute thyroiditis and 90 (67.67%) were PTCs. FNA biopsy results confirmed 52 nodules, including 30 (57.69%) benign nodules, 9 (17.31%) Hashimoto nodules, 2 (3.85%) subacute thyroiditis, and 11 (21.15%) PTCs.
CEUS characteristics analysis
The enhancement intensity, patterns of enhancement, boundary, morphology, and internal homogeneity at enhancement peak (p < 0.05) were significantly different between benign and malignant nodules. However, perfusion defect and size at enhancement peak (p＞ 0.05) showed no significant differences (Table 1). Malignant nodules mainly showed hypoenhancement (73.39%), centripetal enhancement (85.18%), unclear boundary (72.06%), irregular morphology (81.97%), and heterogeneity enhancement (76%). Therefore, we scored according to the CEUS indicators to differentiate between benign and malignant thyroid nodules (Table 2).
Table 1.
Comparison of CEUS characteristics of thyroid nodules
| CEUS qualitative analysis indicators | Malignant (n = 101) | Benign (n = 84) | χ2 value | p-value |
|---|---|---|---|---|
| Enhancement intensity | 62.92 | <0.001 | ||
| Hypoenhancement | 91 | 31 | ||
| Isoenhancement | 8 | 46 | ||
| Hyperenhancement | 2 | 5 | ||
| No enhancement | 0 | 2 | ||
| Patterns of enhancement | 113.92 | <0.001 | ||
| Centrality | 92 | 16 | ||
| Centrifugal | 2 | 2 | ||
| Diffuse | 0 | 4 | ||
| Partiality | 6 | 58 | ||
| Ring | 1 | 4 | ||
| Internal homogeneity | 71.24 | <0.001 | ||
| Homogeneity | 6 | 54 | ||
| Heterogeneity | 95 | 30 | ||
| Perfusion defect | 0.00 | 0.10 | ||
| With | 89 | 74 | ||
| Without | 12 | 10 | ||
| Boundary | 63.18 | <0.001 | ||
| Clear | 3 | 46 | ||
| Unclear | 98 | 38 | ||
| Morphology | 108.29 | <0.001 | ||
| Regular | 1 | 62 | ||
| Irregular | 100 | 22 | ||
| Size | 10.22 | 0.06 | ||
| Enlargement | 5 | 3 | ||
| Invariability | 81 | 79 | ||
| Decrease | 15 | 2 |
CEUS, contrast enhanced ultrasound.
Table 2.
The CEUS thyroid nodules scores
| CEUS qualitative analysis indicators | 1 | 0 |
|---|---|---|
| Enhancement intensity | Hyperenhancement | Isoenhancement, Hypoenhancement, No enhancement |
| Patterns of enhancement | Centrality | Centrifugal, Diffuse, Partiality, Ring |
| Internal homogeneity | Heterogeneity | Homogeneity |
| Boundary | Unclear | Clear |
| Morphology | Irregular | Regular |
CEUS, contrast enhanced ultrasound.
Comparison between ACR TI-RADS and CEUS
As shown in Table 3, all 84 benign nodules were classified as TR3–5 as per the ACR TI-RADS guidelines, with varying degrees of malignancy risk. According to the CEUS score, 76 of these were graded below 5 points, ranging from 0 to 4 points (Figures 2–4), while the remaining 8 scored 5 points. Among the 101 malignant nodules, 9 were classified as TR4 and the remaining 92 as TR5 based on the ACR TI-RADS classification. However, as per the CEUS score, 88 nodules scored five points (Figure 5), and the remaining 13 nodules scored between 1 and 4 points (Table 3). There were statistically significant differences between conventional ultrasound TI-RADS classification and the total scores of CEUS in benign thyroid nodules (Figure 6), but not in malignant thyroid nodules (Figure 7).
Table 3.
Distribution of benign and malignant thyroid nodules in ACR TI-RADS and CEUS
| Scores/Classification | Benign (84) | Malignant (101) | ||
|---|---|---|---|---|
| ACR TI-RADS | CEUS | ACR TI-RADS | CEUS | |
| 0 | 0 | 14 | 0 | 0 |
| 1 | 0 | 29 | 0 | 1 |
| 2 | 0 | 15 | 0 | 2 |
| 3 | 13 | 12 | 0 | 5 |
| 4 | 35 | 6 | 9 | 5 |
| 5 | 36 | 8 | 92 | 88 |
| p-value | 0.000 | 0.289 | ||
ACR, American College of Radiology; CEUS, contrast enhanced ultrasound; TI-RADS, Thyroid Imaging Reporting and Data System.
Figure 2.
Images of the right thyroid lobe acquired in a 61-year-old male. (a) Conventional ultrasound revealed a 7.2 mm nodule (outlined by arrows) that appeared solid (two points), hypoechoic (one point), and with irregular margins (two points), classified as TR4. (b) CEUS only revealed irregular morphology (outlined by arrows, one point); therefore, the total score was one point. (c) Histological analysis confirmed this specimen to be a nodular goitre (original magnification, ×200). CEUS, contrast enhanced ultrasound.
Figure 3.
Images of the left thyroid lobe acquired in a 67-year-old male. (a) Conventional ultrasound revealed a 10 mm nodule (outlined by arrows) that appeared solid (two points), marked hypoechogenicity (three points), and with irregular margins (two points), classified as TR5. (b) CEUS revealed no enhancement, clear boundary, and regular morphology, with a total score of 0. (c) FNA biopsy results confirmed this nodule to be benign (original magnification, ×200). CEUS, contrast enhanced ultrasound; FNA, fine needle aspiration.
Figure 4.
Images of the right thyroid lobe acquired in a 64-year-old female. (a) Conventional ultrasound revealed a 9.4 mm nodule (outlined by arrows) that appeared solid (two points), marked hypoechogenicity (three points), with irregular margins (two points), and taller-than-wide (three points), classified as TR5. (b) CEUS revealed hypo-enhancement (one point), partiality patterns of enhancement (one point), and irregular morphology (one point), with a total score of 3 points. (c) Histological analysis confirmed this specimen to be a nodular goitre (original magnification, ×200). CEUS, contrast enhanced ultrasound.
Figure 5.
Images of the right thyroid lobe acquired in a 25-year-old female. (a) Conventional ultrasound revealed an 8.6 mm nodule (outlined by arrows) that appeared solid (two points), marked hypoechogenicity (three points), with irregular margins (two points), taller-than-wide (three points), and having punctuate echogenic foci (three points), classified as TR5. (b-e) CEUS revealed hypoenhancement (one point), centrality patterns of enhancement (one point), unclear boundary (one point), irregular morphology (one point), and heterogeneity enhancement (one point), with a total score of 5 points. (f) This thyroid nodule was confirmed to be a papillary carcinoma during post-surgical pathological examination (original magnification, ×200). CEUS, contrast enhanced ultrasound.
Figure 6.
The distribution box plot of benign thyroid nodules in ACR TI-RADS and CEUS (p < 0.05). ACR, American College of Radiology; CEUS, contrast enhanced ultrasound; TI-RADS, Thyroid Imaging Reporting and Data System.
Figure 7.
The distribution box plot of malignant thyroid nodules in ACR TI-RADS and CEUS (p＞ 0.05). ACR, American College of Radiology; CEUS, contrast enhanced ultrasound; TI-RADS, Thyroid Imaging Reporting and Data System.
Diagnostic performance of ACR TI-RADS and CEUS
As shown in the ROC curve, the sensitivity, specificity, accuracy, positive predictive value (PPV) and negative predictive value (NPV) of TR5 in the diagnosis of malignant nodules were 90.10%, 55.95%, 74.59%, 72.22%, and 82.46%, respectively. The AUC was 0.738 (95% CI: 0.663–0.813). The sensitivity, specificity, accuracy, PPV, and NPV of 5 points of CEUS qualitative analysis were 86.13%, 89.29%, 87.57%, 90.63%, and 84.27%, respectively. The AUC was 0.916 (95% CI: 0.871–0.961) (Figure 8).
Figure 8.
ROC curves evaluated the diagnostic performance of ACR TI-RADS and CEUS. ACR, American College of Radiology; CEUS, contrast enhanced ultrasound; ROC, receiver operating characteristic; TI-RADS, Thyroid Imaging Reporting and Data System
Discussion
There are many versions of thyroid nodule classification, including the ATA, AACE, ACE, AME, and ACR TI-RADS classification. Previous studies have shown that the 2017 edition of ACR TI-RADS classification has higher diagnostic performance.19,20 In our study, the TR5 category with the highest risk of malignancy in ACR TI-RADS had higher sensitivity (90.10%) and lower specificity (55.95%) in the diagnosis of thyroid malignant nodules. However, Lauria et al19 reported that the specificity of TR5 in predicting malignant nodules was higher (92.1%) and the sensitivity lower (41.7%). The reason for this difference may be related to our study inclusion criteria, as we enrolled all small solid nodules and excluded cystic, mixed cystic, and solid thyroid nodules that were >1 cm. Our study results indicate that CEUS has significantly higher diagnostic performance than ACR-TI-RADS TR5 for differentiating between benign and malignant nodules. The specificity of CEUS qualitative analysis (89.29%) was significantly higher than that of the ACR TI-RADS (55.95%). These findings also indicated that CEUS-based qualitative analysis could more effectively exclude malignant nodules and avoid unnecessary biopsies.
Several studies have shown that CEUS has good sensitivity and specificity in the diagnosis of malignant thyroid nodules.21–23 However, CEUS has not been widely used in clinical practice, because there is no final consensus on the accuracy of CEUS in the diagnosis of thyroid nodules. In our study, hypo-enhancement, unclear boundary at enhancement peak, and heterogeneity enhancement were statistically significant in differentiating benign and malignant thyroid nodules, but the sensitivity of the three indicators were all lower than 80%. Zhan et al24 found that hypoenhancement was the only indicator to predict malignant nodules. However, in our study, the sensitivity of hypoenhancement in diagnosing malignant nodules was not high, which is consistent with the findings of Wang et al.22 Our result could also be supported by another study, which showed that 60% of malignant nodules and 40% of benign nodules show reduced vascularity.25 Furthermore, Liu et al26 found that expansion of the external capsule of malignant nodules resulted in unclear nodule boundaries during enhancement. Foschini et al27 found that heterogeneity enhancement reflected the uneven distribution of blood vessels in malignant nodules. With nodule enlargement, these two conditions are more obvious. Therefore, the selection of nodules ≤1 cm in our study may be the reason for the low sensitivity. The sensitivities of centripetal enhancement and irregular morphology were relatively high, of which, the former’s sensitivity was the highest (85.18%). This is because the neovascularisation of thyroid malignant nodules is divided into central area and marginal area. The vessels in the central area are relatively sparse, while those in the marginal area are relatively dense. The difference in vascular density between the central area and marginal area may lead to the centripetal enhancement.28
Our study has some limitations. First, the study design was retrospective in nature. Second, as the focus of our study was a small solid nodule, selection bias could not be completely ruled out. Third, availability of CEUS examinations between clinics is another limitation.
Conclusion
Our study found that the application of CEUS qualitative analysis had higher diagnostic performance than ACR TI-RADS, and a higher true negative rate than the ACR TI-RADS. We hope this will contribute to the selection of further treatment options for patients. Therefore, CEUS qualitative analysis is a valuable technique for the diagnosis of thyroid small solid nodules.
Contributor Information
Xin Li, Email: lixin198404@163.com.
Feng Gao, Email: gaofeng19870115@163.com.
Fan Li, Email: medicineli@163.com.
Xiao-xia Han, Email: Xiaoxiahan_sono@163.com.
Si-hui Shao, Email: sihui_shao@163.com.
Ming-hua Yao, Email: yaominghua115@163.com.
Chun-xiao Li, Email: lcx198910@126.com.
Jun Zheng, Email: 18796553666@163.com.
Rong Wu, Email: wurong7111@163.com.
Lian-fang Du, Email: lianfang_du@126.com.
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