The present study investigated the association between halo thickness and the incidence of thyroid cancer. The findings show that halo thickness was positively related to the risk of thyroid cancer. The association between the thickness of the halo and the incidence of thyroid cancer was stable between layers.
The incidence of thyroid nodules has risen over the past few years, and according to the World Health Organization's International Agency for Research on Cancer (IARC) GLOBOCAN 2020 Cancer Incidence and Mortality Database, thyroid cancer has risen to ninth in the global ranking of cancer incidence rates [1, 2]. Thyroid cancer can occur at all ages, but the median age of onset is the early 50s, and there is a predominance of females with the disease [11, 12]. In the present study, the mean age of onset of thyroid cancer was 43.05 ± 11.07 years, and 232 (72.5%) were female, which is in agreement with previous studies.
With the development of technology, ultrasound has become the optimal method for diagnosing thyroid nodules, and there is expert consensus on the diagnosis of thyroid cancer. Solid patterns, with markedly hypoechoic, taller than wide, ill-defined margins, and microcalcification, are the five malignant signs of nodules [13–18]. According to the latest C-TIRADS guidelines [19], those with one of these signs can be diagnosed as 4a, 2 as 4b, 3–4 as 4c, and 5 as 5. In this study, univariate logistic analysis revealed that taller than wide, ill-defined margins with microcalcifications were risk factors for thyroid cancer, which is consistent with guidelines. In univariate logistic analysis, we found that nodules located at the isthmus, petal-like calcification, and coexistent Hashimoto's thyroiditis were also risk factors for thyroid cancer. Jasim S et al.[20] found that the location of thyroid nodules was an independent risk factor in predicting thyroid cancer, and the highest risk of cancer was diagnosed for nodules that occurred in the isthmus. Peng Q et al. [21] studied the relationship between a nodule with petal-like calcification and thyroid cancer and found that among 18 patients containing petal-like calcification, all were surgically confirmed to have papillary thyroid carcinoma, and all had metastases to the cervical lymph nodes. Cappellacci F et al. [22] found that Hashimoto's thyroiditis frequently coexists with differentiated thyroid cancer and concluded that Hashimoto's thyroiditis is an independent risk factor for developing thyroid cancer. It has also been shown that thyroid cancers combined with Hashimoto's thyroiditis are less aggressive and have better prognosis than thyroid cancers without Hashimoto's thyroiditis. Therefore, the results of the present study are consistent with previous literature.
A halo is defined as a hypoechoic or anechoic area surrounding a nodule [6], and the results of published literature on halos in differentiating the diagnosis of thyroid nodules are conflicting [23, 24]. Some scholars believe that a thin halo is an important sign of benign lesions, while others have hypothesized that the absence of or a thick halo is a major sign of malignant nodules [25]. Moreover, there is currently no agreed numerical standard for the specific thickness threshold used to separate thin halos from thick halos, with some using 2 mm [26–28] and others 1 mm [29]. In the present study, we used Moon WJ et al. [30] to define thick and thin halos as ≥ 1 mm and < 1 mm, respectively. Based on these criteria, we found that 121 (80.1%) cases in the ≥ 1 mm group were malignant and that the average thickness of the halo was 1.41 ± 0.29 mm; in the < 1 mm group, 86 (50.9%) cases were benign, and the average thickness of the halo was 0.73 ± 0.20 mm. This is consistent with the research conclusions of Zhang et al. [30, 31]. Therefore, it is clear that malignant nodules are more likely to appear as a thick halo. Moreover, in our study, we found that most of the malignant nodules with thick halos were papillary carcinomas, whereas Zhang et al. found that incomplete or inhomogeneous thick halos were more common in follicular carcinomas. The discrepancy may be due to the difference in the populations that we studied, and another reason may be because our pathology department failed to further differentiate between papillary carcinomas and follicular carcinomas.
There are two types of acoustic halos, a hyperechoic halo and a hypoechoic halo, and the hyperechoic halo or hyperechoic halo has different significance in different tissues. In a meta-analysis, Tian et al. [32] found that a hyperechoic halo around a breast mass was predictive of malignancy, with a sensitivity, specificity and area under the curve (AUC) of 0.27, 0.48 and 0.30, respectively, slightly lower than the predictive value of microcalcifications for breast cancer, with a sensitivity, specificity and AUC of 0.31, 0.49 and 0.38, respectively. The reason for this may be the increased angiogenesis in the periphery of the mass, leading to increased microvessel density and invasion of tumor cells into the stroma, causing a desmoplastic reaction [33]. In the liver, however, a hypoechoic halo is an indication of malignancy or metastasis. Abhinaya S et al. [9] found that the hypoechoic halo is a useful indicator of malignancy, especially in differentiating metastases from typical echogenic hemangiomas, with a positive predictive value of up to 95%. Unlike the hyperechoic halo of a breast mass, a hypoechoic halo around the liver is predominantly a peripheral tumor component with a high proliferative index or a compressed hepatic parenchymal rim. Investigators still disagree on the hypoechoic halo around thyroid nodules, as evidenced by the cutoff value of the thick halo and the predictive value of the halo for the nature of the nodule. The results from our multivariate analysis showed that halo thickness ≥ 1 mm was an independent risk factor for thyroid cancer. Compared with < 1 mm, OR = 4.08, 95% CI = 2.47 ~ 6.73 in the crude model, and OR = 3.16, 95% CI = 1.61 ~ 6.19 in the adjusted model. By using 1 mm as the threshold value, we found that the hypoechoic halo had a certain predictive value for thyroid cancer, with an AUC of 0.821 (95% CI: 0.774, 0.868); the sensitivity and specificity were highest when the cutoff value was 1.29 mm, which was 71.53% and 82.51%, respectively. Therefore, clinicians need to pay special attention to the halo surrounding the nodule when differentiating between benign and malignant nodules, especially when the halo is thick.
According to univariate logistic analysis, we found that halos with uneven regularity and without integrity were risk factors for thyroid cancer. The reason for this may be due to fibrous tissue reactions caused by local breakthroughs in tumor cell proliferation and fibrosis, resulting in an irregular, uneven halo on the ultrasound image. Jeong SH et al. [34] made a similar point in a study to identify follicular carcinoma from follicular tumor. Moreover, dotted flow in the halo with hypo-enhancement suggests a lack of vascularity at the site of the acoustic halo, which is similar to the blood supply in malignant nodules. In a study using SMI to study the distribution of blood flow in nodules and halos, Wu Q et al. [35] suggested that the halo consists of parallel collagen fibers, leading to a reduction in the distribution of blood flow.
Most malignant thyroid nodules, especially small nodules with a diameter of less than 1 cm, are dominated by a lack of blood supply, and color Doppler often has difficulty truly showing the distribution of blood flow in the interior of the nodule, in which case contrast-enhanced ultrasound (CEUS) highlights its advantages. CEUS is a pure blood pool imaging technique that allows for real-time dynamic observation of hemodynamic changes in thyroid nodules and their halos, making it an important method for detecting microbleeds in thyroid cancer. Several meta-analyses have found CEUS to be effective in differentiating thyroid cancer from benign lesions [36, 37], and several studies have demonstrated that malignant nodules have a specific CEUS enhancement pattern, such as heterogeneous enhancement or hypoenhancement [38, 39]. In the present study, we found that striped or punctate blood flow signals of nodules, hypo-enhancement, and heterogeneous enhancement of nodules were risk factors for thyroid cancer, which suggests that clinicians should be aware of the importance of encountering nodules with these ultrasound presentations in their work. Notably, we found that the halo surrounding the malignant nodule showed similar manifestations of a malignant nodule, such as dotted blood flow with hypo-enhancement, and this was also one of the first articles to describe the CEUS features of the halo. The final surgical results showed that the halo of malignant nodules is mainly composed of fibrous tissue and lacks a vascular component, which is one of the reasons for the hypoenhancement of the halo.
Our study had some limitations. The evaluation of cases was retrospective, and there was unavoidable selection bias. The retrospective study design prevented us from evaluating sonographic findings in real time, which might have influenced our evaluation of the interpreters. In addition, the small sample size collected may have prevented us from fully assessing their clinical and sonographic characteristics. Although color Doppler imaging and CEUS were performed in all cases in our study, quantitative parametric analysis of CEUS was not performed. Further prospective studies are needed to address these issues.
In conclusion, in this single-center study, we found that hypoechoic halos around nodules were positively associated with the risk of developing thyroid cancer, especially when the thickness was greater than 1.29 mm. A taller than wide shape, an ill-defined margin, microcalcification, a nodule located at the isthmus, petal-like calcification, coexistent Hashimoto's thyroiditis, nodules with uneven regularity, and nodules without halo integrity were risk factors for thyroid cancer.
Figure 1. Flow chart of the present study
Figure 2. Subgroup analyses of the association thickness of halo and thyroid data base from the 2nd Xiangya Hospital. OR,OddsRatio.CI,Confidence Interval.
Figure 3. Diagnostic value of hyperechoic halos for thyroid cancer