According to the 2018 GLOBOCAN report, the global incidence of thyroid cancer is approximately 14.42/100000, and its mortality rate is 0.46/100000; however, the incidence of thyroid cancer in this country is approximately 14.6/100000, and the mortality rate is 0.48/100000, both of which are higher than the global level. Although the vast majority of thyroid cancer is low risk and the prognosis is better[4, 20], CLNM is significantly related to recurrence and poor prognosis[21, 22]. Studies have found that as the number of metastatic lymph nodes increases, the recurrence rate of PTC also increases. Leboulleux reported that the risk of recurrence in patients with > 10 LNMs (21%) was significantly higher than that of patients with 6–10 LNMs (7%) or patients with < 5 LNMs (3%). In addition, in a follow-up study of 621 N1b patients, a metastatic lymph node diameter greater than 3 cm and more than 5 metastatic lymph nodes independently affected patient's disease-free survival time. In the study, when CLNM occurred, ≥ 3 LNMs and the maximum diameter of a metastasis ≥ 0.2 cm were associated with recurrence-free survival (P < 0.05). Patients with more than 5 LNMs had a significantly higher recurrence rate than those with 5 or fewer LNMs. Based on a large number of clinical studies, the more recognized studies define L-VLNMs as > 5 LNMs in a patient or a maximum diameter of any metastatic lymph node ≥ 2 mm.
Among the 6 risk factors included in this study, sex, age, tumour diameter, extrathyroidal extension and multifocal invasion were high-risk factors for L-VLNM in PTC patients, while HT was not significantly related to L-VLNM. A long-term epidemiological survey of thyroid cancer found that the incidence of PTC in female patients was significantly higher than that in males. Although the incidence was lower in men, male patients often had more tumour invasion characteristics and a higher risk of LNM. In previous studies, male sex was considered an independent risk factor for L-VLNM. In this study, male sex was a risk factors that affected L-VLNM. It is still unclear how sex affects the development of L-VLNM in PTC patients. Therefore, male patients should undergo careful risk assessment before and after surgery.
Studies have shown that L-VLNM is more likely to occur in younger patients, and younger age is considered to be related to PTC aggressiveness, such as vascular invasion and LNM. This study further verified that age < 45 years affects L-VLNM in PTC patients. However, in the 12 articles included in this study, there were multiple age categories. In the eighth edition of the American Joint Committee on Cancer (AJCC) guidelines from 2018, the recommended age cut-off point was 55 years old. The study with the largest sample size included in this paper used 45 years as the cut-off point for the study, further validating age < 45 years as a risk factor for L-VLNM in patients with PTC. However, there is currently relatively little data in the literature due to the relatively recent introduction of this classification. Sex and age, as some of the most readily available clinical information, are worthy of further inclusion in studies with larger samples.
Tumour diameter is an important parameter for T staging. Large diameters are frequently associated with higher aggressiveness and a greater the risk of LNM. Compared with patients with smaller tumours, those with larger tumours have a higher possibility of postoperative recurrence, invasion and lymph node metastasis. Ahn, Lee, Zhang, Dong, Wang, Zhao, and Gao proposed that a tumour diameter > 1 cm in non-PTMC patients is a significant risk factor for L-VLNM (OR = 3.99, 95% CI = 3.45–4.62) (Fig. 3c). This is an indication that more treatment may be needed to achieve effective eradication, such as prophylactic lymph node dissection, and should be recommended for patients who require surgery. There are currently different management strategies for PTMC. A meta-analysis of studies involving PTMC by Min, Ahn, Oh, Wu, Shen and Huang showed that a tumour diameter > 0.5 cm was not a risk factor for the development of L-VLNM in PTMC (OR = 2.14, 95% CI = 1.59–2.88) (3d). However, as an increasing number of PTMCs are now being detected through early screening, the demand for precise treatment for PTMC is increasing. However, given the smallest sample size included in this study and because tumour diameter is one of the most intuitive clinical factors with radiography, identifying the right cut-off value and including more cases is the emphasis of current research.
Tumour invasion of the capsule is considered to be an early stage of extrathyroidal extension and often indicates a greater susceptibility for invasion and recurrence as manifestations of the aggressiveness of PTC. Tumour capsule invasion was also found to be an important risk factor for L-VLNM in this study (OR = 3.62, 95% CI = 1.44–9.06). We found that the study by Ahn was the main source of heterogeneity; after the relevant data were removed, the heterogeneity was significantly reduced and the confidence intervals were more reliable (OR = 2.09, 95% CI = 1.77–2.48). Adequate preoperative neck imaging can be useful for assessing the size of the lesion and the distance between the lesion and the capsule.
After reviewing these cases, we suggest that if the PTMC tumour is < 1 cm and is not located close to the capsule and there are no obvious suspected metastatic lymph nodes in the neck, a relatively conservative treatment approach can be adopted. For example, active monitoring with regular outpatient follow-up accompanied by neck ultrasound is effective in reducing overtreatment.
Extrathyroidal extension is closely associated with CLNM and is an important factor in the prognosis and recurrence of patients with PTC. A meta-analysis showed that extrathyroidal extension is a risk factor for CLNM in patients with cN0 stage PTC. Extrathyroidal extension is an independent prognostic factor that affects the disease-free survival of patients and the survival of specific diseases; it significantly elevates the risk of recurrence (23%-40%) and has become a major predictor of poorer prognosis in PTC. The results of this study show that extrathyroidal extension significantly increases the risk of L-VLNM in PTC (OR = 2.31, 95% CI = 1.90–2.82). Preoperative or intraoperative extrathyroidal extension with a small number of positive LNMs or a small maximum diameter of metastatic lymph nodes may be considered an indication to expand the cervical lymph node biopsy as appropriate. If postoperative pathology confirms the presence of extrathyroidal extension but the absence of L-VLNM, patients should be advised to under go more intensive follow-up with strict follow-up and regular review or even 131I radioiodine therapy.
Multifocality is an important biological characteristic of PTC. After analysing the 10 included articles and studying 10132 patients, we found that the risk of L-VLNM was higher for patients with multiple foci than for those with a single focus. However, it is interesting that Wang and Shen found that multifocality was not significantly associated with the occurrence of L-VLNM in PTC at the cN0 stage in a univariate analysis. Numerous studies[30, 31] have also supported this association. In this study, a comprehensive meta-analysis revealed (n = 5132) that multifocality was an important risk factor for L-VLNM in patients with stage cN0 PTC (OR = 2.07, 95% CI = 1.42–3.01) (Fig. 3i), and we believe that the inclusion of multicentre,, large sample data will help to refine the results. This means that prophylactic central lymph node dissection and appropriately relaxing the indications for lateral cervical lymph node dissection are recommended when multiple lesions combined with cN0 disease are identified preoperatively by imaging.
HT is easily diagnosed by medical history, physical examination, elevated thyroid autoantibodies in serum and characteristic ultrasound findings. However, whether HT is related to LNM is still controversial. Previous studies have shown no significant association between PTC combined with HT and LNM. A related meta-analysis of 9369 PTC patients showed that PTC combined with HT was not associated with LNM. It has also been reported that PTC combined with HT has a better prognosis and can prevent LNM in the central and lateral cervical compartments. Moon et al. performed a meta-analysis that included 71 published studies enrolling 44034 participants and concluded that patients with PTC combined with HT showed better clinicopathological characteristics and a better prognosis than patients with PTC without HT. The results of this study (n = 9616) showed that HT was not associated with L-VLNM (Fig. 3e). After excluding the study by Oh, lower heterogeneity and relatively narrow CIs suggested that the results were relatively reliable. The reason for this finding is considered to be related to the fact that HT patients experience long-term, chronic inflammation, which tends to cause the enlargement of the cervical lymph nodes but does not promote L-VLNM. We should therefore be cautious when considering HT as a high-risk factor for cervical lymph node dissection.