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.