Clinical and prognosis value of the number of metastatic lymph nodes in patients with papillary thyroid carcinoma

Papillary thyroid carcinoma (PTC) is the most common type of thyroid carcinoma (TC). It has a low rate of mortality, even in its advanced stages, and an excellent 10-year overall survival [1]. However, the incidence and recurrence rate of PTC is gradually increasing throughout the world [2, 3]. Further, it has been reported that 66.7% of recurrence incidences of PTC occurred between 5 and 10 years after operation [4, 5]. Notably, when recurrence and distant metastasis occur, the treatment of PTC is usually more compliable and difficult. Several previous studies have reported the involvement of central cervical lymph node metastasis (CLNM) and lateral cervical lymph node metastasis (LLNM) in patients with PTC and 80% of long-term recurrence cases have locoregional cervical lymph nodes metastasis (LNM) (pN1) [6‐8]. In addition, several studies have also reported that LNM is a reliable predictor for recurrence [9, 10] and poor prognosis of PTC [7, 11]. However, there are guidelines on the management of PTC proposing different opinions on the management of central cervical lymph nodes (LNs) in different countries and regions [1, 12, 13].

Many researchers [9, 14] have conducted meta-analyses on the risk factors of LNM and found that the risk factors of LNM in PTC patients were inconsistent across different studies. In recent years, more researcher attention is being applied to the features of metastatic LNs, such as the location of metastatic LNs, the number of metastatic lymph nodes (NMLNs), and the maximum diameter of the metastatic LNs and the metastatic LN ratio (mLNR). On the one hand, many scholars have tried to establish a standard for recurrence risk stratification of PTC patients according to the characteristics of metastasis LNs. They found that the risk of recurrence was higher among PTC patients with larger metastatic LNs or higher mLNR [15‐18].

As declared in the most recent American Thyroid Association (ATA) risk stratification system, the recurrence rate of pN1 PTC with ≤ 5 LNs involved or > 5 LNs involved is 5% and 20%, respectively [1]. Nevertheless, in the AJCC TNM staging system [19], postoperative LN involvement was only divided into CLNM alone (pN1a) and LLNM (pN1b). Therefore, many scholars have suggested addition of the features of metastatic LNs into the current American Joint Committee on Cancer (AJCC) staging system [16, 18]. On the other hand, some investigators have also tried to analyze the clinical response and different characteristics of metastatic LNs of patients with PTC. For instance, a previous study conducted by Gao et al. [20] found that excellent therapeutic effect was mainly among patients with lower mLNR and NMLNs.

Determination of patients with high-risk and administration of appropriate treatment are essential in the clinical treatment and management of PTC. The clinical management of cervical LNs for patients with PTC is still controversial because there is no requirement for a minimum number of lymph nodes to be sampled [18]. This retrospective study explored the relationship between the features of LNM and NMLNs as well as the outcome in patients with PTC and hence aimed to provide substantial evidence for the medical practice of PTC with LNM.

Although a good prognostic value of PTC was reported, a rate of recurrence, long-distance metastasis, and disease-specific mortality among patients with PTC who were diagnosed as LNM were also evident [2, 9, 22, 23]. Therefore, knowledge of the characteristic of patients with LNM and the predictors for LNM in patients with PTC is highly required. The purpose of this study was to evaluate the influence of the location of metastatic LNs and NMLNs on prognosis of patients with PTC. Results of the present study found that pN1 patients having aggressive characteristics, such as a larger primary tumor size, the presence of grossly ETE, were related to a greater NMLNs. Moreover, it was also found that RFS among pN1 patients was significantly discrepant between different groups.

Many previous studies have reported that young people are more likely to have LNM [24], the data obtained from the study revealed that patients aged < 55 years old were more prone to NMLNs > 5, especially CLNs > 5. Besides, aged < 55 years old was an independent predictor for the high prevalence of NMLNs > 5 and CLNs > 5. Whether prophylactic CLND should be recommended during thyroidectomy for patients younger than 55 years old is still controversial. On one hand, prophylactic CLND may lead complications that might significantly influence the quality of life [1]. On the other hand, patients older than 45 years old is an independent risk factor for recurrence [25]. Therefore, a balance between the risks and benefits of prophylactic CLND deserves further discussion. We suggest that patients aged between 45 and 55 years old should undergo CLND at the same time of thyroid surgery to reduce the risk of recurrence. In our study, ratio of female /male ratio was 1:3, which was consistent with previous studies [2]. Nevertheless, no relationship was observed between male patients and NMLNs > 5, including CLNs > 5 and LLNs > 5, which were not consistent with the finding previously reported by Sheng et al. [24], who found that male predict an increased number of CLNM (n ≥ 5) in patients with PTMC.

A characteristic relationship between metastatic LNs and the original PTC lesion was also detected. The PTMC, with a diameter ≤ 10 mm, has a better prognosis than PTC [1]. Although investigators alarmed that PTMC might occur in LNM before diagnosis [26], pathological data from patients in our study confirmed that non-PTMC was an independent risk factor for NMLNs > 5, especially for CLNs > 5. This could imply that patients with PTMC were at a low-risk of NMLNs > 5 and CLNs > 5. Besides surgery, active surveillance could also be an alternative approach for patients with PTMC [1]. Hence, a larger tumor size could be a risk factor for worse LN status, which should be a higher concern for the clinicians. Several studies have concluded that patients with LNM are likely associated with bilateral cancer and multifocality [11, 27], it was found that bilaterality was a high-risk factor for NMLNs > 5 and LLNs > 5 in the present study. The determination of the correlation between LN status and ETE is also critical. In our study, NMLNs > 5 was associated with ETE, which was in agreement with several other reports of previous studies [11, 28]. Furthermore, tumor gross ETE was the risk factor for the high prevalence NMLNs > 5, including CLNs > 5 and LLNs > 5. Previous evidence showed that ETE had a severe influence on the prognosis of patients and high prevalence in the aggressive types of thyroid carcinoma, which cannot be overlooked [19, 29]. According to a study conducted by Li et al. [29], the risk of LN involvement in patients without ETE was similar to that of patients with ETE into perithyroidal tissue but lower than those with T3b and ETE invading beyond the strap muscles. Unfortunately, we did not study the relationship between LNM and different extent of ETE.

Numerous works of literature have reported an association of HT with less CLNM [11, 24, 30]. In this study, coexisting HT was not associated with NMLNs > 5, which was found only in 158 patients, hence the results were not sufficient for a substantive conclusion. The presence of BRAF^V600E mutation, common in PTC, was closely related to invasive long-term outcomes of PTC, such as higher disease-specific mortality and a shorter RFS [31‐33]. A previous study proposed a correlation between LN status and BRAF cytology [34, 35], whereas our data demonstrated BRAF^V600E mutation was not relevant to NMLNs > 5. It is important to emphasize that patients with the identification of BRAF^V600E mutation may need more aggressive treatment when there is evidence of LNM, but not if there is no any evidence of LNM [19]. Whether the NMLNs will affect treatment decisions of pN1 patients with a BRAF^V600E mutation is also worthy of further discussion. Prospective studies with a large sample are needed to elucidate the relationship between BRAF^V600E mutation and metastatic LNs to establish the appropriate operational and follow-up strategy for the patients with LNM.

Results of the present study found that pN1 patients with CLN > 5 were associated with advanced tumor stage but not reduce 3-year RFS. On the contrary, pN1 patients with LLNs > 5 were associated with a lower RFS. Of course, there is need for a long-time follow-up to testify this phenomenon. The information obtained from the clinicopathological risk factors, related to NMLNs > 5, should be applied to guide any treatment decisions. LNM is one of the most important factors for lobectomy or total thyroidectomy [1]. It was suggested that lobectomy or total thyroidectomy should be determined in combination with the tumor diameter, LN status, the presence or absence of ETE and etc. Total thyroidectomy is feasible for patients with a diameter ≥ 40 mm ETE and LLNM. It was also emphasized that there should be an intense focus on necessity of CLND for all PTC patients by preoperative evaluation of cervical LN status. Although there is no significant reduction in RFS among patients with CLN > 5, it is an independent risk factor for LLN > 5, which reduces RFS. Consequently, we proposed to perform a selective application of prophylactic CLND for patients with a risk of CLNs > 5 and therapeutic CLND for patients with a risk of LLNs > 5. In addition, thyroid be totally removed and therapeutic CLND as well as MND be simultaneously performed among patients with LLNs > 5. A regular follow-up including cervical US and thyroid function test should also be taken for the high-risk population with NMLNs > 5, especially for LLN > 5. The ATA guidelines recommend RAI for high-risk and some moderate-risk patients, but not for low-risk patients [1]. We suggested that pN1b patients with total thyroidectomy should accept a subsequent RAI treatment, which completely remove tumor and residual thyroid tissue to prevent the recurrence and distant metastasis by promoting sufficient I¹³¹ to enter the residual thyroid tissue and metastatic focus [36, 37]. However, RAI should only be employed in patients with a total thyroidectomy because I¹³¹ can damage normal thyroid tissue [13]. It may be necessary to evaluate NMLNs and estimate the effect of RAI treatment in the future. Next, A certain time and dose levothyroxine should be given as an alternative postoperative therapy to achieve the goal of individualized and dynamic inhibition of TSH as well as reduce the possibility of tumor recurrence [38]. To conclude, the features of metastatic LNs should be cautiously considered in the postoperative risk stratification, guiding treatment decision-making and follow-up practices.

The study had some limitations. Firstly, it was inevitable to avoid the disadvantages of a single-center and retrospective study. Secondly, the clinicopathological characteristics of patients with different sizes of metastatic LNs were not evaluated due to lack of information on the size of metastatic LNs. Thirdly, the lack of data on 10-years follow-up of disease recurrence and survival prevented the evaluation of the relationship between LN status and recurrence as well as survival.

However, this article is still worthy of reference, especially in the analysis of the characteristics of metastatic LNs in patients with PTC. A larger sample size was enrolled and only patients with PTC who had a total checked number of LNs ≥ 5 were retrieved so that the data made difference to assessing the influence of CLN > 5 and LLN > 5 on the clinicopathological characteristics of patients with PTC. In the future, multiple-center and long-term prospective studies are proposed to clarify the correlation between LN status and various clinicopathological parameters in patients with PTC as well as evaluate the influence of LNM on prognosis.

Overall, our findings showed that CLNs > 5 was more common in patients with age < 55 years old, largely tumor diameter and tumor gross ETE. LLNs > 5 was more common in patients with age < 55 years old, bilaterality, CLNs > 5, tumor gross ETE and more inclined to have a reduced RFS. However, there is need for sufficient clinical data and molecular biology theory to support the described argument. Further studies on the characteristics of LNM will be essential for prognostic judgment and decision-making in clinical practices to improve the health of patients.