According to the EFSUMB guidelines, CEUS is a promising non-invasive method for differentiating benign and malignant thyroid nodules. The type and severity of tumors can be determined by analyzing the distribution characteristics, enhancement degree, and time intensity curve (TIC) of contrast agents in the lesions. However, the data of CEUS qualitative and quantitative evaluation parameters overlap with the data of benign and malignant nodule standards; thus, the interpretation of tumor micro-vessels may be challenging. Therefore, when evaluating thyroid nodules, clinical data, conventional ultrasound, and other imaging findings should be combined for interpretation to improve diagnostic accuracy [13].
Tumor blood vessels are heterogeneous. There are differences between tumor blood vessels and non-tumor blood vessels. Also, benign and malignant tumors with different pathological classifications, pathological proceses, and regions of the same type of tumor may have different blood vessels [14]. Because of the high interstitial pressure in the tumor, more blood vessels are compressed and collapsed, so the blood supply in the tumor is reduced [15]. Therefore, some scholars have focused their attention on the area around the tumor. Relevant literature reports on the area around breast and liver tumors have provided new characteristic auxiliary information for clinical use, which can help surgeons make more correct surgical decisions. This study examined the interior of thyroid nodules and the peripheral ultrasound contrast parameter information of thyroid nodules in order to improve the diagnostic accuracy of ultrasound contrast and benefit patients.
Some studies [8, 16–19] suggested that hypo enhancement is closely related to malignant tumors, which is consistent with our data. In this study, the proportion of hypo enhancement in malignant nodules (66.3%) was significantly higher than in benign nodules (21.7%), which may be due to the following aspects: first, because the proportion of cancer nodules ≤ 10mm in this study was large (69.1%), small tumors did not form a large number of mature tumor vascular beds, and the blood supply was insufficient, and in turn, no obvious perfusion was seen [18, 20, 21]. Secondly, papillary thyroid carcinoma often shows dense interstitial fibrosis [22]. The increase of blood vessels is usually related to cell proliferation in the tumor state, and fibrosis reduces the vascular density in the nodules [22, 23]. Therefore, nodule CEUS is more likely to present hypo enhancement.
According to the Guidelines for the Diagnosis and Treatment of Adult Thyroid Nodules and Differentiated Thyroid Cancer issued by the American Thyroid Association (ATA) in 2015 and the Chinese Guidelines for the Ultrasonic Malignancy Risk Stratification of Thyroid Nodules (C-TIRADS) issued by China in 2020, irregular or unclear edges in conventional ultrasound are important indicators for the diagnosis of malignant nodules [24, 25]. Yi et al. [12] found that unclear margins after contrast enhancement are an independent risk factor for malignant thyroid tumors. Consistent with this study, the proportion of unclear margins after contrast ultrasound in DTC (47.4%) was also significantly higher than that of benign nodules (6.1%). The analysis of the causes may be related to the invasiveness of the tumor. CEUS focuses on the analysis of the microvascular pattern. The characteristics of the tumor lead to the tumor invading outwards, while the peripheral area of the lesion is relatively dense, and the tumor is easy to invade outwards, so it will appear unclear in CEUS [20].
Some scholars [26–28] found that uneven enhancement is more common in malignant thyroid tumors. Moreover, Zhang et al. [27] found that ring enhancement was predictive of benign lesions, whereas heterogeneous enhancement was helpful for detecting malignant lesions, also, the CEUS enhancement has a diagnostic sensitivity specificity and accuracy of 88.2%, 92.5%, and 90.4%, respectively. Consistent with the results of this study, 131 of 175 malignant nodules showed uneven enhancement (74.9%), which may be due to neovascularization. Generally speaking, the neovascularization of malignant lesions is divided into peripheral and central areas, and their vascular distribution is different. The blood vessels in the central area are relatively sparse, which is prone to incomplete or complete necrosis. The distribution of new blood vessels in the whole lesion is uneven and complex, which may lead to uneven enhancement [20].
This study found no significant difference in the AUC of malignant thyroid nodules. Yet, other quantitative parameters of the inner and outer edges of the thyroid gland showed statistical significance, which to some extent, indicated a difference between the inner and outer edges of the thyroid. Further refining of the benign and malignant nodules revealed that the peak in the malignant nodules was significantly lower than that in the benign nodules, and there were significant differences between single and multiple factors. It is possible that the differentiation of new blood supply in the malignant nodules was poor, the distribution was uneven, or the micro-vessels were not completely established, so distribution was disordered, dense, and distorted, as well as the calcification, necrosis or fibrosis in the nodules caused the internal perfusion intensity to be lower than the outer edge. Therefore, when this manifestation occurs, it is necessary to consider the possibility of malignancy. Recent studies [29] found that the proportion (46.15%) of malignant nodules R-AS > 1 (the ratio of nodule's ascending slope to surrounding normal thyroid tissue's ascending slope) was significantly higher than that of benign nodules (12.86%) (p < 0.001), indicating that the ascending slope of malignant nodules was significantly higher than that of benign nodules, which is not consistent with our results. Although the mean value of sharpness in malignant nodules is higher than in benign nodules, the difference is insignificant (p = 0.180). On the contrary, sharpness at the outer edge of malignant nodules was significantly lower than that in benign nodules (p < 0.001), which indicated that the perfusion speed at the outer edge of malignant nodules was slow. The analysis may be that most benign nodules are parenchyma thyroid tissue divided into nodules by fibrous tissue due to the infiltration of many lymphocytes. There was no significant difference between the peripheral thyroid tissue and the peripheral thyroid tissue in histopathology, suggesting that the peripheral blood flow perfusion speed was no different from the peripheral thyroid tissue. The biological behavior of malignant nodules was characterized by invasive growth, destruction of surrounding tissues, destruction of normal blood supply, obstruction, or even interruption of blood flow from the outer edge [20]. Jiang et al. [30] quantitatively analyzed CEUS on thyroid nodules and found that papillary thyroid carcinoma showed slow enhancement.
Lei et al. [31] found a difference in age benign and malignant thyroid nodules, which was consistent with our data. Hughes et al. [32] considered that the most common PTC tumor is PTMC over 45 years old, which was different from our findings. In our study, patients younger than 45 accounted for more than 52.0% of DTC cases and only 27.0% of benign cases. These differences among studies may be explained as follows: first, different pathological types were explored. The former mainly studied a PTC in DTC, while the latter mainly investigated the DTC. Second, the younger DTC was reported by some scholars [33]. Under the same environment, the risk of thyroid nodules increases significantly with the decrease in exposure age. Third, with the diversification of detection methods, the high sensitivity of detection instruments, and the improvement of people's health awareness, the detection rate increases significantly, making some thyroid nodules appear earlier [34, 35].
In this study, it was also found that the proportion of malignant nodules (69.1%) ≤ 10mm was significantly higher than that of benign nodules (28.7%), which was consistent with the research of Zheng and other scholars [36].
The present study has some limitations. First, this was a retrospective, single-center study with a relatively small sample size. Second, the operating physician's ROI profile in the process of angiographic analysis was not completely consistent. Finally, although the average value was taken, the deviation still existed, so a more scientific method should be tested in the future.