Diagnostic value of CEUS combined with C-TIRADS for indeterminate FNA cytological thyroid nodules

Abstract

OBJECTIVES:

To investigate the diagnostic value of CEUS combined with C-TIRADS for indeterminate FNA cytological thyroid nodules.

METHODS:

The clinical data, ultrasonic images, C-TIRADS categories and CEUS images of 192 patients with indeterminate FNA cytological thyroid nodules confirmed by the surgical pathology were analyzed retrospectively. The diagnostic efficacy of CEUS, C-TIRADS and CEUS-TIRADS were calculated.

RESULTS:

The AUCs of CEUS, C-TIRADS and CEUS-TIRADS were 0.905 (95% CI: 0.862∼0.949), 0.881 (95% CI: 0.825∼0.938) and 0.954 (95% CI: 0.922∼0.986), respectively. The sensitivity, specificity, PPV, NPV, accuracy, LR^– and LR⁺ were 84.7% (116/137), 85.5% (47/55), 93.5% (116/124), 69.1% (47/68), 84.9% (163/192), 0.179, 5.82 and 84.7% (116/137), 83.6% (46/55), 92.8% (116/125), 68.7% (46/67), 84.4% (162/192), 0.183, 5.17, 92.7% (127/137), 89.1% (49/55), 95.5% (127/133), 83.1% (49/59), 91.7% (176/192), 0.082, and 8.50, respectively. Compared with CEUS and C-TIRADS, CEUS-TIRADS had improved the AUC, sensitivity and accuracy (all P < 0.05).

CONCLUSIONS:

CEUS and C-TIRADS had high diagnostic values in indeterminate FNA cytological thyroid nodules. CEUS-TIRADS improved AUC, diagnostic sensitivity and accuracy, and helped to distinguish indeterminate FNA cytological nodules.

Keywords

Thyroid nodule contrast enhanced ultrasound Chinese thyroid imaging reporting and system

1 Introdution

The Chinese thyroid imaging reporting and data system (C-TIRADS) was launched in 2020 [1]. C-TIRADS has been widely used in major hospitals recently and is gradually being popularized in grassroots hospitals in China. Contrast enhanced ultrasound (CEUS) could show the distribution of microvessels of thyroid nodules, which was helpful for the differential diagnosis of nodules [2]. However, C-TIRADS did not pay attention to the distribution of microvessels of thytoid nodules. So the combination of C-TIRADS and CEUS can compensate for this deficiency. Fine needle aspiration (FNA) was carried out in many hospitals, but sometimes the cytological results were unclear, and it was often necessary to repeat FNA or coarse needle biopsy(CNB), even surgical resection. To research the diagnostic value of CEUS combined with C-TIRADS in the diagnosis of indeterminate FNA cytological thyroid nodules, the ultrasonic images and CEUS images of 192 cases of indeterminate FNA cytological nodules confirmed by surgerical pathology were retrospectively analyzed.

2 Methods

2.1 Patients

From October 2021 to April 2024, there were 351 patients with indeterminate FNA cytological thyroid nodules confirmed by surgerical pathology. There were inclusion criteria: (1) Age ≥18 years; (2) The FNA cytological results of thyroid nodules were unclear (Bethesda III, IV or V); (3) Thyroid ultrasound examination and CEUS were underdone before surgical operation; (4)The informed consent was signed before FNA, CEUS and surgical operation; (5) The largest diameter of nodule >5 mm. A total of 198 patients met the inclusion criteria. There were exclusion criteria: (1) patients with contraindications of CEUS (n = 2); (2) nodules with coarse calcification or peripheral calcification or microcalcification like blizzard (n = 4). For the patient with multiple nodules, the most suspicious nodule was selected. Finally, 192 nodules of 192 patients were included in this study.

2.2 2D-US and CEUS

MyLab twice ultrasonic diagnostic instrument (Esaote, Italy) with 4∼13 mHz probe (LA523) was used. The examinations were performed by two radiologists who had been engaged in thyroid ultrasound diagnosis for more than 10 years and thyroid CEUS for more than 2 years.

The patient maintained supine position, and exposed the neck. The shape, echo, boundary, calcification and aspect ratio of thyroid nodules were observed, and satisfactory images were selected for storage. When displaying the best longitudinal section of the nodule (showing the complete nodule and the surrounding thyroid), the contrast mode was used, 2 ml SonoVue injection was injected through the elbow vein quickly. We observed dynamic images for 3 min and stored them for further analysis.

2.3 FNA operation and categories

FNA operation was as follows: (1) Patient lied supine with head tilted back; (2) Neck skin was disinfected with iodophor and local anesthetized with 2% lidocaine; (3) By ultrasound guidance,we punctured the target nodule by a 5 ml empty syringe; (4) The syringe was slightly lifted and inserted for 5∼10 times under appropriate negative pressure; (5) The syringe was pulled out, and the cell fluid was smeared and quickly fixed. The above process was repeated 2∼3 times.

According to the thyroid cytopathology Bethesda System (TBSRTC), FNA cytopathology was divided into six categories [3]. The indeterminate FNA cytopathology included AUS/FLUS (Bethesda III), FN/SFN (Bethesda IV) and Suspicious for malignancy (Bethesda V) in this study.

2.4 C-TIRADS categories

Blind review was performed by 2 radiologists who had been engaged in thyroid ultrasound diagnosis for more than 10 years. Different views were settled through consultation.

According to the classification standard of C-TIRADS, there were five malignant ultrasound features (solid,markedly hypoechoic, blurred / irregulary boundary or extrathyroid invasion, microcalcification and vertical orientation), and each of those was one point. If there was the comet tail artifact (one of ultrasonic features of benign nodules), the total score would be reduced one point. If there was the microcalcification at the same time, the total score would be increased one point. Finally, the total score of the nodule determined the category: 1 (no nodule, no score), 2 (–1 point, benign), 3 (0 point, probably benign), 4A (1 point, low suspicion), 4B (2 points, moderate suspicion), 4C (3∼4 points, high suspicion), 5 (5 points, highly suggestive of malignancy) and category 6 (biopsy proved malignant) [1, 4].

2.5 CEUS analysis

CEUS analyzed enhancement intensity (hyper-enhancement, iso-enhancement and hypo-enhancement), enhancement pattern (centripetal, centrifugal and diffuse), enhancement uniformity (homogeneous and heterogeneous), boundary after enhancement (blurred and smooth), ring enhancement (absent and present) and wash-out (earlier, later and equal) [5].

2.6 CEUS-TIRADS (CEUS combined with C-TIRADS) analysis

If CEUS showed the benign enhancement mode (smooth boundary, iso-enhancement / hyper-enhancement and ring enhancement), the TI-RADS category was reduced by one category, unless the nodule originally belonged to category 2 or below. If CEUS showed the malignant enhancement mode (blurred boundary and hypo-enhancement), the TI-RADS category was increased by one category. If CEUS was ambiguous (blurred boundary or hypo-enhancement), the TI-RADS category remained unchanged (Figs. 1, 2).

Fig. 1

The case of a 36-year-old woman with a 8.8×5.6×8.7 mm solid hypoechoic nodule in the left lobe of the thyroid. (A) Conventional two dimensional image showed that the nodule had one malignant indicator (solid) and C- TIRADS classified category 4A. CEUS image showed hyper-enhancement and smooth enhancement boundary. CEUS-TIRADS classified category 3. (B) Pathological image of the lesion, a nodular goiter.

Fig. 2

The case of a 32-year-old woman with a 8.4×7.3×7.7 mm solid, markedly hypoechoic nodule in the left lobe of the thyroid. (A) Conventional two dimensional image showed that the nodule had three malignant indicators (solid, markedly hypoechoic, extrathyroid invasion) and C- TIRADS classified category 4C. CEUS image showed hypo-enhancement and blurred boundary. CEUS-TIRADS classified category 5. (B) Pathological image of the lesion, a PTC.

2.7 Statistical analysis

SPSS 20.0 (USA) and MedCalc 18.5 (Belgium) were used for statistical analysis. The receiver operating characteristic (ROC) curves were drawn and determined the diagnostic threshold of CEUS, C-TIRADS and CEUS-TIRADS. Normal quantitative indexes (such as age) and non normal quantitative indexes (such as nodule size) were compares by t-test and Mann-Whitney test respectively. The diagnostic efficacy and sex ratio were compared by χ² test. P < 0.05 was considered to be statistically significant.

3 Results

3.1 Postoperative pathological results and clinical data

A total of 192 patients included 40 males and 152 females, and aged 22∼77 (47.0±13.5) years. The maximum diameter of thyroid nodule was 5.0∼31.0 mm. 192 thyoid nodules were confirmed by surgery and pathology, including 55 benign nodules (36 nodular goiter, 4 chronic lymphocytic thyroiditis, 5 Hashimoto nodules, 2 subacute thyroiditis, 5 follicular adenomas and 3 adenomatous goiter) and 137 malignant ones (132 thyroid papillary carcinoma, 3 follicular thyroid carcinoma, 2 medullary carcinoma). The difference in patient age between benign and malignant nodules was statistically significant (t = 2.86, P = 0.005), and the differences in patient sex ratio and nodule size were not statistically significant (χ² = 0.998, P = 0.318; Z = 0.131, P = 0.896).

3.2 CEUS features of thyroid nodules

The differences in CEUS characteristics between malignant and benign nodules were statistically significant (all P < 0.05, Table 1). The main manifestations of malignant nodules were hypo-enhancement (73.0%), centripetal enhancement (76.6%), heterogeneous enhancement (84.7.%), blurred boundary after enhancement (81.8%), absent ring enhancement (91.2%), and earlier wash-out (67.9%). While benign nodules showed ring enhancement (72.7%) and later and equal wash-out (85.5%).

Table 1
CEUS features of thyroid nodules

Features Benign (n = 55) Malignant (n = 137) χ ² P

Enhancement intensity Hypo-enhancement 11 100 51.416 <0.001

Iso-enhancement 30 33

Hyper-enhancement 14 4

Enhancement pattern Centripetal 32 105 10.363 0.006

Centrifugal 3 11

Diffuse 20 21

Enhancement uniformity Homogeneous 35 21 44.330 <0.001

Heterogeneous 20 116

Boundary after enhancement Smooth 43 25 61.630 <0.001

Blurred 12 112

Ring enhancement Present 40 12 81.317 <0.001

Absent 15 125

Wash-out Earlier 8 93 45.324 <0.001

Later 33 28

Equal 14 16

	Features	Benign (n = 55)	Malignant (n = 137)	χ ²	P
Enhancement intensity	Hypo-enhancement	11	100	51.416	<0.001
	Iso-enhancement	30	33
	Hyper-enhancement	14	4
Enhancement pattern	Centripetal	32	105	10.363	0.006
	Centrifugal	3	11
	Diffuse	20	21
Enhancement uniformity	Homogeneous	35	21	44.330	<0.001
	Heterogeneous	20	116
Boundary after enhancement	Smooth	43	25	61.630	<0.001
	Blurred	12	112
Ring enhancement	Present	40	12	81.317	<0.001
	Absent	15	125
Wash-out	Earlier	8	93	45.324	<0.001
	Later	33	28
	Equal	14	16

3.3 Diagnostic efficacy of CEUS, C-TIRADS and CEUS-TIRADS

ROC curves manifested that the optimal thresholds of C-TIRADS and CEUS-TIRADS were > category 4B. For C-TIRADS and CEUS-TIRADS, nodules of category 4C and 5 were diagnosed as malignancy and those of category 2, 3, 4A and 4B were determined as benignity. ROC curves demonstrated the AUC of CEUS, C-TIRADS and CEUS-TIRADS were 0.905, 0.881 and 0.954, respectively (Fig. 3). The diagnostic performance indicators were shown in Table 2.

Fig. 3

ROC curves for CEUS, C-TIRADS and combined method (CEUS-TIRADS). The area under the ROC curve (AUC,95% CI) of CEUS, C-TIRADS and CEUS-TIRADS were 0.905 (95% CI: 0.862∼0.949), 0.881 (95% CI: 0.825∼0.938) and 0.954 (95% CI: 0.922∼0.986), respectively.

Table 2

Diagnostic efficacy of CEUS, C-TIRADS and CEUS-TIRADS

Method	Pathology		Sensitivity %	Specificity %	NPV %	PPV %	Accuracy %	LR⁺	LR^–
	Benign	Malignant
CEUS	–	47	21	84.7	85.5	69.1	93.5	84.9	5.82	0.179
	+	8	116
C-TIRADS	–	46	21	84.7	83.6	68.7	92.8	84.4	5.17	0.183
	+	9	116
CEUS-TIRADS	–	49	10	92.7	89.1	83.1	95.5	91.7	8.50	0.082
	+	6	127

CEUS: contrast-enhanced ultrasound; C-TIRADS: Chinese thyroid imaging reporting and data system; NPV: negative predict value; PPV: positive predict value; LR⁺: positive likelihood ratio; LR^–: negative likelihood ratio.

3.4 Comparison of diagnostic efficiency of CEUS-TIRADS, C-TIRADS and CEUS

Compared with CEUS and C-TIRADS, CEUS-TIRADS had improved the AUC, sensitivity and accuracy (all P < 0.05). The differences in the diagnostic specificity, NPV and PPV were not statistically significant (P > 0.05 for all) (Table 3).

Table 3
Comparison of diagnostic efficacy of CEUS-TIRADS, C-TIRADS and CEUS

Sensitivity Specificity NPV PPV Accuracy

CEUS vs. C-TIRADS χ ² 0.000 0.070 0.003 0.055 0.020

P 1.00 0.792 0.954 0.815 0.887

CEUS-TIRADS vs. CEUS χ ² 4.401 0.327 3.324 0.469 4.254

P 0.036 0.567 0.068 0.493 0.039

CEUS-TIRADS vs. C-TIRADS χ ² 4.401 0.695 3.504 0.851 4.841

P 0.036 0.405 0.061 0.356 0.028

		Sensitivity	Specificity	NPV	PPV	Accuracy
CEUS vs. C-TIRADS	χ ²	0.000	0.070	0.003	0.055	0.020
	P	1.00	0.792	0.954	0.815	0.887
CEUS-TIRADS vs. CEUS	χ ²	4.401	0.327	3.324	0.469	4.254
	P	0.036	0.567	0.068	0.493	0.039
CEUS-TIRADS vs. C-TIRADS	χ ²	4.401	0.695	3.504	0.851	4.841
	P	0.036	0.405	0.061	0.356	0.028

CEUS: contrast-enhanced ultrasound; C-TIRADS: Chinese thyroid imaging reporting and data system; NPV: negative predict value; PPV: positive predict value.

4 Discussion

CEUS could dynamically observe the microvascularization of thyroid nodules, improve the diagnostic efficiency of thyroid nodules, and reduce unnecessary surgical operations by generating scattered echoes and enhancing blood flow signals through contrast agent microbubbles [6, 7]. Some studies showed that hypo-enhancement was highly correlated with malignant thyroid nodules [2 , 9]. In our study, hypo-enhancement appeared in 73.0% of malignant nodules and in only 20% of benign ones. Blurred / irregulary boundary on 2D ultrasound was one of diagnostic indicators for malignant thyroid nodules [1]. Blurred boundary after enhancement on CEUS was also an important malignant indicator [10]. In our study, blurred boundary after enhancement appeared in 81.8% of malignant nodules and in 21.8% of benign ones. CEUS mainly reflected the microcirculatory perfusion mode of the tumor. The malignant tumor invaded outwards easily because the microvasculature in the peripheral area of the malignant tumor was relatively dense. The blurred boundary after enhancement might reflect the aggressiveness of the malignant tumor [2]. The uneven neovascularization in the entire tumor might be the reason for heterogeneous enhancement [11]. Xi X et al insisted that heterogeneous enhancement appeared more frequently in malignant thyroid nodules [12]. This study revealed that CEUS features of malignant thyroid nodules were mainly hypo-enhancement (73.0%, 100/137), heterogeneous enhancement (84.7%, 116/137), blurred boundary after enhancement (81.8%, 112/137) and earlier wash-out (67.9%, 93/137), while those of benign nodules were mainly ring enhancement (72.7%, 40/55), iso-enhancement / hyper-enhancement (80.0%, 44/55), and later / equal wash-out (85.5%, 47/55). Among 132 papillary thyroid carcinoma nodules, 117 nodules exhibited two or more of the four malignant features identified by CEUS. This should be related to the pathological characteristics of papillary thyroid carcinoma (PTC). Wang G et al. reported that for the diagnosis of atypical-enhanced PTC, the combination of enhancement characteristics and time intensity curve (TIC) of CEUS had a good clinical application value [13].

In 2020, the Chinese Medical Association launched the TI-RADS suitable for the actual situation in China. Its main advantages were that it was easy to operate, meet the clinical needs, and had a high differential diagnostic value for thyroid nodules. Our study indicated that the ACU was 0.881, the diagnostic sensitivity, specificity, accuracy, LR⁺ and LR^– were 84.7% (116/137), 83.6% (46/55), 84.3% (162/192), 5.17 and 0.183, respectively, which were similar to the relevant reports [14 –16].

CEUS combined with C-TIRADS helped to distinguish thyroid nodules. Cao H et al considered that the differential diagnosis value of CEUS combined with C-TIRADS for thyroid nodules was higher than that of C-TIRADS alone [17]. Cheng H et al adjusted the classification of C-TIRADS category 4 thyroid nodules by CEUS, and the result showed that the diagnostic performance after adjustment was significantly improved [18]. Thyroid nodule FNA was carried out in many hospitals. Although many studies focused on the over-treatment of thyroid nodules, the patient with unclear FNA cytopathology could benefit from an accurate diagnosis, which could prevent additional psychological stress to the patient. It was very important to improve the differential diagnostic value for thyroid nodule with indeterminate cytology. In our study, the AUC, the diagnostic sensitivity and accuracy of CEUS-CTIRADS were significantly higher than those of the two methods alone, which was line with the results of some studies [5 , 20].

Huang Y et al. reported that VueBox^® was a helpful tool for the evaluation of dynamic microvascularization of thyroid nodules, and dynamic contrast enhanced ultrasound (DCE-US) using VueBox^® perfusion analysis could provide added values for differential diagnosis of small solid thyroid nodules (≤1.0 cm) [21]. Jung EM et al reported that multimodal ultrasound diagnostics supported by artificial intelligence-optimized B-mode, elastography, and contrast-enhanced ultrasonography parametric and with perfusion imaging had a high diagnostic potential for the evaluation of solid thyroid lesions [22]. Zhong L reported that the nomogram based on conventional ultrasound imaging in combination with shear wave velocity (SWV) ratio had the potential for preoperative cervical lymph node metastasis (CLNM) risk assessment [23]. Whether it could be combined with other technologies, such as artificial intelligence (AI), ultrasound elastography and BRAF gene detection, needed to be further explored.

The shortcomings of this study were as follows: (1) There was inevitably selection bias in this retrospective study. (2) The retrospective analysis of the characteristics of CEUS had different degrees of subjectivity. In future studies, quantitative indicators such as peak time would be added. (3) It was necessary to increase the sample size for further research on nodules with different sizes and FNA cytology results (Bethesda III / IV / V). (4) This study didn’t enroll and investigate patients with FNA determined and correctly diagnosed thyroid nodules, which might cause to overestimate the diagnostic efficacy of CEUS and C-TIRADS.

5 Conclusions

CEUS and C-TIRADS had diagnostic values for indeterminate FNA cytological thyroid nodules. The combination could improve the sensitivity, accuracy and AUC, which helped to distinguish indeterminate FNA cytological thyroid nodules.

Conflict of interest

The authors declare no conflicts of interest.

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