Although a good prognostic value of PTC was reported, recurrence, metastasis, and death among PTC patients were also evident [2, 18]. PTC patients with LNM have a higher rate of recurrence and disease-specific mortality [7, 19]. Therefore, knowledge of the characteristic of patients with LNM and the predictors for LNM in PTC patient is highly required. The purpose of this study was to evaluate the influence of the location of metastatic LNs and NMLNs on prognosis of PTC patients. We found a significant correlation between several prognostic variables and LNM and NMLNs >5. Patients with LNM and a greater NMLNs were related to aggressive characteristics, such as a larger primary tumor size, the presence of grossly ETE. We also found RFS was a significantly difference between PTC patients with NMLNs ≤5 and PTC patients with NMLNs >5.
Old age is a risk factor for poor prognosis of PTC patients [15, 20] and a recent AJCC TNM staging system used a 55-years cutoff to upstage patients. Whereas Jeon et al. [21] reported that patients aged ≥45 years were at a higher risk of LNM; other studies revealed that young people are also more likely to have LNM [22]. Our data revealed that patients aged <55 years were more prone to LNM and NMLNs >5 and ten-year age was an independent predictor for the low prevalence of LNM and NMLNs >5. However, Spinelli et al. [23] retrospectively discussed the clinical characteristics of 132 children and adolescents with PTC and found that age was not related to LNM. These results vary from ours due to difference in the target population. In this study, however, we sampled PTC patients of all ages, which could provide reliable evidence that LNM and NMLNs >5 were frequent in young patients. Prophylactic CLND should be recommended during thyroidectomy for patients younger than 55 years old. Nevertheless, prophylactic CLND may lead complications that could significantly influence the quality of life [1]. Therefore, a balance between the risks and benefits of prophylactic CLND deserves further discussion. The association between gender with LNM is controversial. Results and findings from similar studies are inconsistent. In many studies, the association between male and CLNM were significant [22]. However, Spinelli et al. [23] reported no significant correlation. In our study, ratio of female /male ratio was 1:3, which was consistent with previous studies [2]. We found that male patients were susceptible to LNM but also an independent predictor for the high prevalence LNM. However, no relationship was observed between male patients and NMLNs >5. Our results were similar but not identical to the finding reported by Sheng et al. [22], who found that male predict increased a high number of CLNM (n ≥5) in PTMC patients.
We detected a characteristic relationship between metastatic LNs and the original PTC lesion. PTMC, with a diameter ≤10 mm, has a better prognosis than PTC [1]. Although investigators alarmed that PTMC might occur in LNM before diagnosis [24], pathological data from patients in our study confirmed that non-PTMC was more inclined to LNM and NMLNs >5. This could imply that patients with PTMC were low-risk. In addition, besides surgery, active surveillance could be an alternative approach for PTMC patients [1]. The tumor diameter of above 20 mm indicates the aggressiveness of PTC [1]. However, the effect of the tumor size on LNM in PTC varies greatly among different studies [24, 25]. In the present study, patients with a largely tumor diameter were prone to LNM and NMLNs >5. Furthermore, tumor size per 10mm was an independent risk factor for LNM and NMLNs >5. Hence, a larger tumor size could be a risk factor for worse LN status, which should be more concerned by clinicians. Several studies have concluded that patients with LNM are likely associated with bilateral cancer and multifocality [9, 26], but the correlation between bilaterality and multifocality and NMLNs have been rarely conducted. And the impact of these two factors on metastatic LNs remains controversial [22]. We found that LNM and NMLNs >5 were associated with bilaterality. Whereas bilaterality was a high-risk factor for NMLNs >5, multifocality wasn’t a high-risk factor for neither LNM nor NMLNs>5. The determination of the correlation between LN status and ETE is also critical. In our study, LNM and NMLNs >5 was associated with ETE, which was similar to previous reports [9, 27]. Furthermore, tumor gross ETE was the risk factor for the high prevalence LNM and NMLNs >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 [15, 28]. Li et al. [28] stated that 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 reported an association of HT with less CLNM [9, 22, 29]. In this study, coexisting HT was not associated with LNM and 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, causing change of valine-to-glutamic acid, resulting in an activation of the BRAF protein kinase and the microtubule-associated protein (MAP) kinase pathway, plays an important role in the progression and aggressiveness of PTC [30]. A previous study proposed a correlation between LN status and BRAF cytology [31]. Our data demonstrated BRAF-V600E mutation was not apparently relevant to LNM and NMLNs >5 in PTC patients. Sheng et al. [22] and Zhang et al. [32] also noted that BRAF-V600E mutation was not related to CLNM. But a rarely little research has been performed in this field regarding the relationship between BRAF-V600E mutation and the NMLNs. The inconsistency in reporting the association between BRAF-V600E mutation and LNM could be, to some extent, attributed to variation in mutation rates [31, 33, 34]. A BRAF-V600E mutation was closely related to invasive long-term outcome, such as a higher disease-specific mortality and a shorter RFS [35, 36]. It is important to emphasize that patients with the identification of BRAF-V600E mutation may need more aggressive treatment when there is the evidence of LNM, but not if there is no LNM [15]. Xing et.al [30] also pointed out that the application of the prognosis of mutations should be employed to meet the personalized needs of specific clinical conditions. If the NMLNs will affect treatment decisions of pN1 patient 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 strategy for patients with LNM.
As stated in previous studies, a larger size of metastatic LNs, or an increase in NMLNs, or a higher positive mLNR was associated with a higher risk of recurrence and reduced long-term survival [12, 13, 37, 38]. In the AJCC TNM staging system [15], postoperative LN involvement was only divided into pN1a and pN1b. Incorporating size of metastatic LNs, NMLNs and mLNR into the current AJCC staging system may improve the stratification of the risk groups [8, 12, 39]. However, the criteria for selecting the minimal number of examined LNs and the mLNR cut-off value have not been completely determined [6, 16, 17]. PTC patients with LNM were associated with advanced tumor stage. In contrast, pN1 patients with NMLNs >5 weren’t associated with advanced tumor stage. Nevertheless, we emphasize an intense focus on NMLNs because 3-year RFS was significantly different between different NMLNs groups. Therefore, the features of metastatic LNs should be cautiously considered in the postoperative risk stratification even pN1 patients with low TNM staging.
Our research had several limitations. Firstly, it was inevitable to avoid the disadvantages of a single center and retrospective study. Secondly, we did not evaluate clinicopathological characteristics of patients with different sizes of metastatic LNs because of lack 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 and survival. Even so, this article is still worthy of reference, especially in the analysis of the characteristics of metastatic LNs in PTC patients. We enrolled a larger sample size and only retrieved PTC patients who had total checked number of LNs ≥5 so that our data made difference to assessing the influence of LN status especially NMLNs on the clinicopathological characteristics of PTC patients. In the future, multiple-center and long-term prospective studies are proposed to clarify the correlation between LN status and various clinicopathological parameters in PTC patients and evaluate the influence of LNM on prognosis.
Overall, our findings suggested that LNM was frequent in patients with younger age, male gender, largely tumor diameter and tumor gross ETE. NMLNs >5 was more common in pN1 patients with younger age, largely tumor diameter, bilaterality and tumor gross ETE and more incline to have a reduced RFS. Certainly, sufficient clinical data and molecular biology theory to support this argument is required. To summarize, the information obtained from the clinicopathological risk factors, related to LNM and NMLNs>5, should be applied prognostically to guide subsequent treatment decisions, including the selective application of prophylactic CLND or additional treatment. Further studies on the characteristics of LNM will essential for prognostic judgment and decision-making in clinical practices to improve the health of patients.