Diagnostic value of contrast-enhanced ultrasound in preoperative evaluation of lymph node metastasis and thyroid nodules in papillary thyroid carcinoma: a single-center retrospective study 

Abstract

Background

The contrast-enhanced ultrasound (CEUS) has been recently used for the assessment of cervical lymph node metastasis to guide the surgical operation in the patient with papillary thyroid carcinoma (PTC). However, the specificity and sensitivity of CEUS reported from previous studies is not consistent. The objective of this study was to evaluate the diagnostic value of CEUS to the metastasis of cervical lymph node in PTC patients based on the data from one regional central hospital.

Methods

The diagnostic value of CEUS in preoperative LNM of PTC patients was concluded by comparing the results of CEUS on lymph node status with postoperative pathology examination. In addition, this study conducted hierarchical analysis of PTC patients to explore whether tumor size, different lymph node regions, and hashimoto's thyroiditis have an influence on the assessment of CEUS.

Results

This research enrolled 965 PTC patients finally, including 266 male and 699 female patients with a mean age of 42.27±11.34 years. 527 patients were supposed to be clinical-node negative and 438 were clinical-node positive before surgery. The specificity, sensitivity, PPV, NPV and accuracy of CEUS in the assessment of LNM in PTC patients were 56.00%, 71.00%, 57.06%, 69.76% and 62.59% respectively. For central and lateral lymph node, the accuracy of CEUS in PTC patients were 49.43% and 54.30%, respectively. Besides, it was showed that the accuracy of CEUS in PTC patients with HT slightly dropped to 58.44%, and the accuracy of CEUS in PTC patients with non-HT in turns increased to 64.17%. The accuracy of CEUS in non-PTMC and PTMC patients were 65.68% and 61.24%, respectively. The accuracy of CEUS in predicting central lymph node metastases was statistically different in PTC patients with or without Hashimoto's thyroiditis(P＜0.001) in this study, but not in lateral lymph nodes (P=0.114).

Conclusion

The accuracy of CEUS on the assessment of LNM in PTC is not consistently satisfactory, especially for central lymph nodes, small tumor diameter, or the patient with HT. More diagnostic technologies for abnormal lymph node should be considered in PTC patients.

Introduction

Papillary thyroid carcinoma (PTC) is the most common type of thyroid cancer with an increasing incidence in recent years [1]. PTC is characterized by a predisposition of metastasis to cervical lymph node, and previous studies [2–3] showed that the incidences of lymph node metastasis (LNM) could reach 30%-80%. In addition, LNM is often associated with local recurrence and distant metastases [4]. Therefore, complete dissection of suspicious abnormal lymph nodes is one of important methods to reduce the possibility of the recurrence of PTC.

Accurate preoperative assessment of cervical lymph node metastasis (LNM) is very important for patients with PTC. There are many technologies to evaluate cervical lymph nodes preoperatively, such as CT, MRI, and ultrasonography (US). It is not very satisfactory and efficient to identify abnormal lymph node using the spatial resolution and contrast resolution of CT in PTC patients [5]. Although MRI has some value in the assessment of lymph node metastasis, it is not currently available as a routine preoperative examination due to its high price. Ultrasound (US) which is recommended by American Thyroid Association (ATA) [6] to be the first choice for the diagnosis of thyroid cancer has been recently used for the evaluation of cervical LNM in patients with PTC. Nevertheless, it is not reliable and accurate for the assessment of cervical LNM by US [4, 7]. Previous studies [8–9] reported that only 20–31% of PTC patients with cervical LNM can be accurately detected by US.

In recent years, contrast-enhanced ultrasound (CEUS) has been developed rapidly to assess and diagnosis of thyroid cancer. Zhang et al. [10] has showed that CEUS had high specificity and contributed to diagnose thyroid nodules. Moreover, previous studies reported that CEUS has high sensitivity and specificity for lymph node metastasis of PTC. But the results coming from different regions are not consistent and the application of CEUS in the evaluation of LNM is controversial. The objective of this study was to evaluate the diagnostic value of CEUS to the metastasis of cervical lymph node and thyroid nodules in patients with PTC.

Materials and Methods

Patients

The Clinical and pathological data of PTC patients who all were performed contrast-enhanced ultrasound (CEUS) before surgery were collected from January 2019 to January 2020. The following patients were excluded: (i) incomplete data, (ii) history of thyroid surgery, (iii) benign thyroid tumor and (iv) others types of carcinoma. A total of 965 patients were enrolled in this research (Figure 1). All PTC patients have received thyroid lobectomy or total thyroidectomy, combined with ipsilateral central lymph node dissection (CLND). Some patients received prophylactic or therapeutic lateral lymph node dissection (LLDN). Thyroid gland and lymph nodes that were removed during the operation were submitted for postoperative pathological examination. The results were independently diagnosed by two pathologists with more than 10 years of experience. If the result is in doubt, the diagnosis is made by a more experienced pathologist. The diagnostic value of CEUS in preoperative suspicious lymph nodes metastasis (LNM) of PTC patients was concluded by comparing the results of CEUS on lymph node status with postoperative pathology examination. In addition, hierarchical analysis was carried out to estimate the diagnostic value of CEUS in the subgroups as follows: (i)Hashimoto's thyroiditis (HT) and non-Hashimoto's thyroiditis (non-HT), (ii) papillary thyroid microcarcinoma (PTMC) and non-papillary thyroid microcarcinoma (non-PTMC) and (iii) lymph nodes in different regions (central and lateral). 

Contrast-enhanced ultrasound (CEUS)

All individuals underwent preoperative CEUC. The contrast agent (SonoVue, Bracco, Italy) was mixed with 5 mL of saline, and 1.4-1.5 mL of the mixed suspension was rapidly pushed into the patient’s peripheral vein. Then, images were collected at the time of injection of the contrast agent and the time was not less than one minute. The imaging data obtained from CEUS were continuously stored. All individuals were monitored for adverse events until 20 min after the procedure. Finally, the images were discriminated by the sonographer. Based on the ultrasound features of LNM in thyroid cancer suggested by previous studies [8-10,14], we used the following signs as a condition for diagnosing metastatic lymph nodes: centripetal perfusion, heterogeneous enhancement. The following images show ultrasonogram sonography of clear metastatic lymph nodes (Figure 2) and benign lymph nodes (Figure 3), and images of lymph nodes with unclear diagnosis (Figure 4). CEUS was performed by sonographers with at least 5 years of experience in the assessment of the thyroid nodule and its draining regional lymph nodes. 

Statistical analysis 

T-test, mean±standard deviation, chi-square, or Fisher’s exact test were employed to draw a comparison about the gender differences (male, female), age (< 55, ³ 55 years), tumor size (£ 10, <10 mm), Bilaterality (yes, no), Hashimoto’s thyroiditis (yes, no) in the PTC patients. Multivariate analysis was performed to explore factors linked with central l lymph node metastasis in PTC patients. Specificity (= true negative/(false positive + true negative)´100%), sensitivity(= true positive/(true positive + false negative) ´100%), positive predictive value (PPV= true positive/(true positive + false positive) ´ 110%), negative predictive value (NPV= true negative/(true positive + false positive) ´ 110%) and accuracy were used to evaluate the value of CEUS in the diagnosis of lymph node metastasis (LNM). SPSS version 22 software was employed for all analyses, and P＜0.05 was taken as statistically significant. 

Results

The clinical features of patients

This research enrolled 965 PTC patients finally, including 266 male and 699 female patients with a mean age of 42.27 ± 11.34 years. All the patients were evaluated by CEUS, in which 527 patients were supposed to be clinical-node negative (cN0) and 438 were clinical-node positive (cN1) before surgery. In this study, 627 (64.97%) were papillary thyroid microcarcinoma (PTMC), and 231 (23.94%) were Hashimoto's thyroiditis identified by pathological examination, among which 178 (18.45%) were bilaterality and 7 (0.73%) were isthmus. The incidence of LNM in 965 PTC patients was 56.48% (545/956) (Table 1).

Risk factor of central lymph node metastasis

The percentage of central lymph node metastasis (CLNM) was 53.58% (517/965) in this article. The factors which are statistically related to central LNM may have influence on the assessment of CEUS on suspicious LNM before surgery. In the univariate analysis, the results revealed that the factors including male (p<0.001), tumor size >10mm (p<0.001) and bilaterality (p = 0.001) were significantly correlated with central LNM in PTC patients. However, age (p = 0.116) and HT (p = 0.472) were not correlated with central LNM. In addition, multivariate analysis showed that male (p<0.001, OR:1.792, 95%CI: 1.316–2.439), tumor size >10mm (p<0.001, OR: 3.163, 95%CI: 2.370–4.222) and bilaterality (p = 0.011, OR: 1.585, 95%CI: 1.112–2.260) were independent risk factors for central LNM in PTC patients (Table 2).

Diagnostic value of CEUS to lymph node metastasis

In this study, the specificity, sensitivity, PPV, NPV and accuracy of CEUS in the assessment of LNM in PTC patients were 56.00%, 71.00%, 57.06%, 69.76% and 62.59% respectively. For central and lateral lymph node, the accuracy of CEUS in PTC patients was 49.43% and 54.30%, respectively (Table 3).

To identify whether HT and anatomical division of neck would affect the evaluation of CEUS on suspicious LNM, Hierarchical analysis was performed. The results showed that the accuracy of CEUS in PTC patients with HT slightly dropped to 58.44%, and the accuracy of CEUS in PTC patients with non-HT in turns increased to 64.17% (Table 3). In 231 PTC patients with HT, for central and lateral lymph node, the accuracy of CEUS was 45.89% and 53.33%, respectively. Besides, in 734 PTC patients with non-HT, the accuracy of CEUS was 66.62% and 54.64%, respectively (Table 4).

Diagnostic value of CEUS to PTMC and different LNM diameter

The accuracy of CEUS in non-PTMC and PTMC patients were 65.68% and 61.24%, respectively (Table 3). Besides, the metastatic lymph node diameter of these patients was selected and analyzed. The result showed that the larger the diameter of LNM, the high sensitivity of CEUS in PTC patients (Table 5).

Discussion

A clinical characteristic of papillary thyroid carcinoma (PTC) is the predisposition of metastasis to neck lymph node [11]. However, because of the small size and special position, the assessment of metastatic lymph node by conventional US in patients with PTC is limited and unsatisfactory [7]. Previous studies showed that the sensitivity of US for cervical LNM is less than 50% [12–13]. CEUS is a new imaging modality that has high sensitivity for vascularity of tissue, enabling assessments of blood perfusion [14–15], and it provide more useful information than conventional US. Previous experiences indicated that Vascularity patterns and their changes are very important in distinguishing between benign and malignant thyroid nodes. CEUS is increasingly being used to assess lymph nodes in patients with PTC before surgery [16–17].

Our study retrospectively analyzed CEUS counting in 965 patients with PTC, and the results showed that the accuracy of CEUS in the assessment of LNM in PTC patients were 62.80%. This result is significantly lower than previous researches [14, 18–19] (Chen et al. 89.1%, Hong et al. 89.3%, Wei et al. 70.8%). The possible reason is that the analysis of previous studies just based on a very small size of population. Our study also indicated that the negative predictive value (NPV) of CEUS assessing lymph node metastasis in 965 individuals with PTC were 70.17%, which was also unexpectable. The precise judgement of metastatic lymph node is very important to the decision of how to perform surgery in the patient with PTC. This precise treatment would favor in reducing the surgical trauma and tumor recurrence after surgery. The disputation on which anatomical region of cervical lymph node should be resected isn’t resolved because of the lack of prospective clinical trials. For the patient with cN0, prophylactic lymphadenectomy is not recommended according to American and European guidelines[5, 20], and if lymph node was considered to be metastatic before surgery, then therapeutic dissection of lymph node is considered necessarily. Preoperative diagnosis always determines the individualized surgical treatment, and the thoroughness of the initial operation usually correlates with the lower incidence of tumor recurrence. According to the results of this study, the false negative rate of lymph node metastasis of PTC evaluated by CEUS assessment is about 30%, which may lead to inadequate initial surgery for some patients and increased local recurrence rate. To resolve this problem, frozen section examination (FSE) was suggested and could quickly assess the status of the neck lymph node during the process of surgery, which would help surgeons to better determine the scope of surgery (total thyroidectomy or thyroid lobectomy, ipsilateral central lymph nodes dissection or bilateral central lymph nodes dissection). Moreover, FSE could decrease the risk of recurrence, theoretically. Raffaelli et al. [21] showed that FSE is able to change the extent of thyroidectomy in about one-fourth of PTC patients scheduled for thyroid lobectomy, and it’s overall accuracy can reach 90%. Unfortunately, due to the long time and high cost of FSE, it has not been fully applied.

According to our analysis, the central lymph node is more difficult to evaluate when compared to the lateral lymph node. Moreover, the central lymph nodes are the most likely areas for metastasis of PTC [11], which is also proved by our database (the data not shown). Central lymph node dissection is usually prone to serious complications including the injury of recurrent laryngeal nerve, temporary or permanent dysfunction of parathyroid and esophagotracheal leakage. It is important to know the status of lymph nodes before operation. Previous studies have explained many factors associated with CLNM, such as tumor size >2 cm [22], age <45 years [23], capsule invasion [24], multifocality [24, 25], male [26] and so on. In our research, the clinical data of 965 patients with PTC were analyzed. The results showed that male, tumor size >1cm, and bilaterality were served as independent risk factors associated with CLNM. It is suggested that more comprehensive preoperative evaluation should be considered for the PTC patients when these conditions mentioned above are presented.

Hashimoto's thyroiditis (HT) is one of the factors which would affect the accuracy of CEUS. HT is a common autoimmune thyroid disease which usually destroys thyroid cells through lymphocytic infiltration and interstitial fibrosis, eventually leading to hypothyroidism. The relationship between HT and lymph node metastasis of PTC has been controversial. Previous article [27] reported that the patients of PTC coexists with HT have higher aggressiveness. However, some authors [24, 28–29] have demonstrated that PTC of HT no relationship between tumor aggressiveness, and associated with lower rates of recurrence and longer overall survival. Besides, it might be a protective factor for lymph node metastasis in PTC [30]. Our result showed no association between HT and lymph node metastasis of PTC.

Moreover, HT can also lead to inflammatory enlargement of regional lymph nodes, which increases the difficulty of preoperative evaluation of lymph node status in PTC patients by US [31, 32]. Few studies have investigated the predictive value of CEUS for the status of lymph node in PTC patients with coexistent HT. In our study, all patients were differentiated according to different clinicopathological features to explore the difference in the accuracy of CEUS. It was indicated that the accuracy (58.44% vs 64.17%) and sensitivity (62.68% vs 75.34%) of CEUS in assessing lymph nodes in patients with HT was significantly reduced compared with non-HT patients. Moreover, the accuracy (45.89% vs 66.62%), specificity (45.45% vs 67.25%) and sensitivity (46.60% vs 64.38%) of CEUS on the CLNM in the patients with HT was significantly reduced when compared with that in the ones without HT. In addition, the accuracy of CEUS was statistically different in PTC patients with or without Hashimoto's thyroiditis(P<0.001). As respect to the evaluation of LLNM by CEUS, no significant difference was found (P = 0.114). The results suggested that the value of CEUS was significantly affected in the evaluation of lymph nodes in PTC patients with HT, especially in central lymph nodes.

Based on the previous literatures and our knowledge, the possible reasons for the results above may be indicated as follows: ⅰ. The deep anatomical position of central lymph nodes makes the accuracy of assessment unsatisfactory; ⅱ. Compared with other cancers, PTC is relatively inert, and lymph node metastasis is unobvious and small; ⅲ. The central lymph node is close to the thyroid gland, and HT leads to inflammatory enlargement of local lymph nodes, which is not easy to distinguish from metastasis. These reasons may explain why CEUS is more accurate in assessing lymph nodes in the lateral region and the patients without HT.

Conclusion

The precise evaluation of lymph node metastasis is the most important part of preoperative examination for thyroid carcinoma. CEUS has been applied not only for the evaluation of thyroid nodules but also in the assessment of metastatic lymph node. However, the accuracy is not consistently satisfactory according to our study, especially for central lymph nodes with HT patients, small tumor diameter. Inaccurate assessment may further leads to unnecessary total thyroidectomy plus cervical lymph nodes dissection, or incomplete dissection of lymph nodes. It is recommended that other techniques like contrast-enhanced CT/MR and intraoperative pathological biopsy of suspicious lymph nodes should be considered in addition to CEUS.

Declarations

Authors’ contributions 

Conception and design of the research: Ni Chen and Xuedong Yin. Performed data collection: Zhixin Yang, Tao Tao and Ni Chen. Analyzed the data: Xiaofeng Wang, Jiali Zou and Long Wang. Contributed reagents, materials, or analysis tools: Tao Tao, Zhu Qiu and Huimin Du. Contributed to the writing of the manuscript: Zhixin Yang, Xiaofeng Wang and Tao Tao. All authors reviewed the manuscript.

Acknowledgments 

The authors would like to thank all the surgeons who were participating in the surgical operations of PTC patients, namely Dr. Xinliang Su, Dr. Hongyuan Li, Dr. Shengchun Liu, and Dr. Xiaoyi Wang. The authors would like to thank all the pathologists who were involved in the diagnosis of PTC and LNM in this study, namely Dr. Yaying Yang, Dr. Xiaoqin Guan and Dr. Shanshan Yu. Besides, the authors would like to thank all the medical ultrasound doctors who were participating in the CEUS examination for PTC patients, namely Dr. Chong Zhong and Dr. Yong Zhang.

Disclosure statement

Huimin Du received the funding support from Chongqing Medical Scientific Research Project. All the authors are working at nonprofit institutes, and declared no conflict of interest. 

Funding

The study was supported by Chongqing medical scientific research project (NO.2021MSXM033). 

Availability of data and materials

All data generated or analysed during this study are included in this published article and its supplementary file.

Ethics approval and consent to participate

All human data and experimental protocols were carried out in accordance with the Declaration of Helsinki, and this retrospective study was approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University. The informed consents were obtained from all the patients when they were admitted to our hospital. 

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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