As far as we are aware, there haven't been many studies done on the risk factors for LLNM in cN0 PTMC patients, particularly those with sizable sample sizes from a single centre [6, 10, 11, 12]. In this retrospective analysis, we looked into the risk variables for LLNM using data from 4872 individuals with cN0 PTMC. According to earlier research (ranging from 3.7 to 7.5%), the rate of occult LLNM was reported to be 3.2% [6, 12]. Multifocality has been identified in earlier research as a risk factor for LNM in PTMC [17, 18]. The LLNM rate was substantially higher (4.7%; 153/3249, p = 0.006) in patients with multifocal PTMC, according to our analysis of the relationship between multifocality and the LLNM rate. Multivariate analysis did not, however, reveal multifocality to be a separate risk factor (data not shown). After that, we solely included patients with unifocal PTMC to look at LLNM risk factors.
For differentiated thyroid carcinoma, primary tumour size is a known prognostic factor [8, 17, 18], and earlier research found a substantial link between a higher risk of LNM and greater tumour size [19]. Tumour size was revealed to be a significant factor related to LLNM by Yon et al. in their assessment of 490 individuals with PTMC [20, 21]. The significant tumour size cutoff value in our study was determined by ROC curve analysis to be 7.5 mm, and patients were subsequently separated into two groups (7 mm and > 7 mm). Tumour size > 7 mm was revealed to be an independent risk factor for LLNM, and the rates of LLNM in these two groups were found to be 1.9% and 6.3%, respectively, with significant differences in both univariate and multivariate analyses. While other studies revealed that tumour size > 5 mm was an independent predictor of the high prevalence of LLNM [17, 21], Zhang et al. [18] evaluated 1066 PTMC patients and found that tumour size > 6 mm was substantially linked with LLNM. Different population demographics and sample sizes may be to blame for the heterogeneity in tumour size cutoff values among researchers. Additionally, all of the patients included in our analysis had unifocal tumours, which would have affected how the cutoff value was determined.
It is well known that the location of the tumour influences both the frequency and seriousness of lymph node metastasis. Tumours in the upper thyroid lobe frequently metastasize to the lateral neck [22, 23, 24], and tumour location in the upper third of the thyroid lobe was discovered to be an independent risk factor for LLNM [22]. This is because the superior thyroid artery facilitates the flow of lymphatic fluid, which encourages the spread of tumour cells. In addition, we discovered that patients with tumours in the upper lobe experienced a considerably higher incidence of LLNM (5.1% vs. 2.7%) than individuals with tumours in the middle and lower lobes. Additionally, multivariate analysis supported prior research findings [18, 21, 23, 24, 25] that the tumour site in the upper lobe was an independent risk factor for LLNM.
The extrathyroidal extension (ETE) is a significant risk factor for LNM and one of the most important prognostic indicators for PTC [8, 10]. Tumours with macro-ETE that invade strap muscles or organs are restaged as T3b or T4 in the eighth edition staging method (2017), while tumours with micro-ETE are staged as T1/2 (4 cm) or T3a (> 4 cm) [16]. According to studies, microscopic ETE is still a reliable indicator of LLNM [17, 25–30]. In our research, we analysed both micro- and macro-ETE. Patients with ETE had a 4.4% LLNM incidence, while patients without ETE had a 2.3% incidence. Both univariate and multivariate analyses revealed these differences to be statistically significant. Patients with macro-ETE (3.6%) and those with micro-ETE or intrathyroidal tumours (3.2%, p = 0.832) did not differ significantly from one another. In a similar vein, Back K discovered no correlation between macro-ETE and LLNM [21]. The small sample size of macro-ETE in individuals with cN0 PTMC may be to blame for this. Recent research has shown that preoperative ultrasonography (US) examination-detected tumours close to the thyroid capsule and thyroid capsule discontinuity are separate risk factors for LLNM in PTMC patients [25, 26]. Tumours with ETE must be tightly associated with the thyroid capsule under US examination, even though we did not analyse the preoperative US characteristics of the tumours. Therefore, based on the preoperative US scan, the link between the tumour and thyroid capsule, as well as the tumour location as previously discussed, it is possible to determine the chance of LLNM.
Previous research has established CLNM as a significant risk factor for LLNM [17, 20, 25, 27]. According to Lim et al.'s research, LLNM was substantially related to the typical proportion of positive LNs in the central compartment [20, 30]. In the current investigation, we discovered that patients with 1–2 CLNMs or 3 CLNMs had a significantly higher risk of LLNM than patients without CLNMs (OR = 2.91, 95% CI 1.93–4.42; p 0.001). Patients with > 5 positive CLNMs had a greater risk of LLNM, according to Bohec et al. [27]. A recent study at our centre found that the number of CLNMs (> 3) was strongly associated with lateral neck recurrence in patients with pN1a PTC [29, 30]. CLNM was also discovered to be a predictor for lateral neck recurrence in PTC patients [28]. As a result, we think that the quantity of CLNM is a useful indicator of the likelihood of LLNM.
In the current cohort analysis, characteristics such as tumour location in the upper lobe, tumour size greater than 7 mm, ETE, and CLNM, particularly 3 positive LNs, were found to be independent risk factors for LLNM of cN0 unifocal PTMC. Based on these variables, we developed a nomogram with a high likelihood of LLNM (AUC = 89.611) and great predictive value (AUC = 0.777). For patients with PTMC, this nomogram can help forecast the likelihood of LLNM, choose a personalised surgical approach, and direct surgeons to carefully assess the lateral neck during follow-up.
Our study has limitations, including those that come with being a nonrandomized, retrospective cohort study. To avoid missing cases of subclinical LLNM, LND was only carried out in patients who had enlarged LNs identified by preoperative ultrasonography and diagnosed as positive by frozen pathology. The current study's strength was that it was carried out in a single medical facility with a sizable sample size and stringent inclusion criteria, producing accurate results.
In conclusion, ETE, CLNMs, particularly three or more, and upper lobe tumour sites and sizes higher than 7 mm were independent risk factors for LLNM in cN0 unifocal PTMC. The chance of LLNM can be calculated and predicted using a nomogram. Therefore, to reduce selection bias and confirm our findings, a prospective multicenter investigation is required.