The relationship between the extent of extrathyroidal extension and lymph node metastasis based on propensity score matching analysis

Introduction

With an anticipated 9.1% age-standardized rate, 8,21,214 incident cases of thyroid cancer (TC) were reported worldwide in 2022, placing it seventh among all malignant tumors. Papillary thyroid carcinoma (PTC) accounts for approximately 95% of all TC cases (1-3).

The treatment of TC mainly relies on surgery, with the choice of surgical approach influenced by various factors. Among these, lymph node metastasis (LNM) and extrathyroidal extension (ETE) are two critical clinical factors. LNM is considered one of the key indicators for assessing the prognosis and treatment plan for TC patients. Factors such as the number, size and location of metastatic lymph nodes often directly impact the choice of surgical approach (4). ETE refers to the invasion of tumor cells into tissues and structures adjacent to the gland, occurring in approximately 13% to 30% of patients (5,6), and is considered a crucial factor affecting the extent of surgical resection and the risk of postoperative recurrence. In cases of more extensive invasion, more extensive surgical resection may be required. However, although it is widely believed that both factors significantly influence the surgical approach, the relationship between LNM and ETE remains controversial in existing studies.

A large number of studies have shown that ETE is a high-risk factor for LNM. For example, a study by Tian et al. (7) indicated that ETE is an independent risk factor for central and lateral LNM. Wu et al. (8) support the above view, suggesting that ETE increases the risk of LNM, as well as the risk of local recurrence and distant metastasis postoperatively, while decreasing postoperative survival rates. Bortz et al. (9) found that different levels of ETE are associated with an increased risk of lymph node and distant metastasis. We hypothesize that, similar to how tumor size within a certain range affects the extent of LNM (10), the degree of LNM may increase as the extent of ETE deepens.

However, some studies have not found a correlation between ETE and LNM. A study by Chen et al. (11) found no significant correlation between ETE and LNM. Koo et al. (12) also reached the same conclusion. The conflicting results may be due to the presence of other risk factors that simultaneously affect LNM.

Therefore, this study aims to explore the clinical correlation between different degrees of ETE and LNM in PTC patients through propensity score matching (PSM) by controlling for confounding factors. It is expected to provide a reference and guidance for the clinical classification of PTC patients and the extent of lymph node dissection. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-319/rc).

Methods

Patients

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University (No. 2025-169-01) and informed consent was waived because there was no patient interest or privacy breach in the form of disclosure of personal information. Clinical and pathological data were collected from 1,487 consecutive patients who underwent at least one side of thyroid lobectomy and ipsilateral central lymph node dissection at the Breast and Thyroid Surgery Department of the First Affiliated Hospital of Chongqing Medical University, Chongqing, China, between January 2023 and June 2024. Incomplete data, diagnosed with non-PTC based on postoperative pathology, underwent reoperation or had a history of other head and neck surgeries, did not undergo lymph node dissection, and had distant metastasis were among the factors that precluded patients from participation. Ultimately, 1,045 eligible individuals were included in this study (Figure 1).

Figure 1 PTC patients exclusion flowchart. ETE, extrathyroidal extension; LND, lymph node dissection; LNM, lymph node metastasis; PSM, propensity score matching; PTC, papillary thyroid carcinoma.

Demographic and clinicopathological data

The collected clinical and pathological data included: gender, age, body mass index (BMI), tumor size, tumor location, tumor side, presence of Hashimoto’s thyroiditis (HT), ETE, multifocal, and LNM. ETE was confirmed by intraoperative or postoperative pathology. The largest lesion diameter and location were recorded as the size and location. Tumor size and location were described in the preoperative ultrasonography report. Multifocal and HT were recorded in both preoperative and intraoperative data. LNM includes metastasis to both central and lateral lymph nodes, as confirmed by postoperative pathology.

Histologically, ETE is classified into three levels based on the degree of invasion. Micro-ETE refers to the extension detected under the microscope, limited to the thyroid capsule. Minimal ETE involves the perithyroidal soft tissue or sternothyroid muscles. Macro-ETE involves extension to the subcutaneous soft tissue, larynx, trachea, esophagus, or recurrent laryngeal nerve (13,14).

Statistical analysis

The statistical analysis was performed using SPSS 25.0 software. The potential risk factors for LNM and ETE were first analyzed using univariate chi-square (χ²) tests, followed by multivariate analysis using binary logistic regression. The significance level was set at α=0.05.

R software was used to perform PSM. To balance the baseline characteristics between the ETE group and non-ETE group, as well as between the LNM group and non-LNM group, we applied a 1:1 nearest-neighbor algorithm without replacement, setting the caliper width at 0.03 on the logit scale (~3% of the pooled standard deviation). This threshold was selected after comparing 0.01, 0.03, and 0.05 in pilot analyses: 0.03 achieved satisfactory balance—indicated by an average standardized absolute mean difference <0.1 (values <0.2 are commonly acceptable; Figures 2,3). In the original dataset, 168 patients had ETE. After matching, 128 patients with ETE were successfully matched with 128 patients with non-ETE, 321 patients with LNM were successfully matched with 321 patients with non-LNM, and binary logistic regression analysis was conducted to examine the relationship between ETE and LNM.

Figure 2 The standardized mean difference in the entire cohort and the matched cohorts. This figure demonstrates that there are balanced covariates between the ETE and non-ETE groups in the matched cohort. ETE, extrathyroidal extension.

Figure 3 The standardized mean difference in the entire cohort and the matched cohorts. This figure demonstrates that there are balanced covariates between the LNM and non-LNM groups in the matched cohort. LNM, lymph node metastasis.

Results

Clinicopathologic characteristics

The majority of 1,045 patients were female (801, 76.7%), with a male-to-female ratio of 1:3.3. The patients’ age ranged from 8 to 84 years (median =41.0 years). The tumor size ranged from 2.3 to 72.0 mm, with a median size of 8.0 mm. Intraoperative and postoperative pathological examination revealed 877 patients (83.9%) with non-ETE and 168 patients (16.1%) with ETE. Postoperative pathological results indicated 462 patients (44.2%) without LNM and 583 patients (55.8%) with LNM. Table 1 provides additional information.

Univariate and multivariate analyses influencing LNM in PTC and PSM

Univariate and multivariate analyses influencing LNM in PTC

The results of univariate analysis revealed that male, age <45 years, tumor size ≥8 mm, ETE, and multifocal were significantly more likely to present with LNM compared to female, age ≥45 years, tumor size <8 mm, non-ETE, and non-multifocal, with statistical significance observed for all (P<0.05). No significant association was found between tumor location, side, or the presence of HT and LNM in PTC patients (P>0.05), as shown in Tables 2,3. Further multivariate logistic regression analysis revealed that male, age <45 years, tumor size ≥8 mm, ETE [odds ratio (OR): 1.791] and multifocal were independent risk factors for LNM (all P<0.05), as shown in Table 3. After stratifying ETE, multivariate analysis showed that only minimal ETE was an independent risk factor for LNM (P<0.05), as shown in Table 4.

It is noteworthy that in our dataset, the distribution of ETE was as follows: micro ETE (83, 7.9%), minimal ETE (54, 5.2%), and macro ETE (31, 3.0%). In univariate logistic analysis, we found that different degrees of ETE were all associated with LNM (P<0.05). However, further multivariate logistic analysis revealed that only minimal ETE was an independent risk factor for LNM (P<0.05).

PSM and analysis

In the multivariate analysis, the OR for ETE was close to 1, which generally suggested that this factor has a minimal impact on LNM and may not have a significant effect. Therefore, we used PSM analysis to explore the relationship between the two factors. After matching age, sex, tumor size and multifocal, our cohort included 256 patients with 128 patients in each group. Table 5 shows the characteristics of each group. After matching, there were no significant difference in the clinicopathological features between the two groups. Further binary logistic regression analysis revealed no significant relationship between varying degrees of ETE and LNM (P>0.05) (Table 6), suggesting that the initial estimate may have been confounded by covariates such as tumor size, age, and multifocal, which were disproportionately distributed in patients with minimal ETE.

Univariate and multivariate analyses influencing ETE in PTC and PSM

Univariate and multivariate analyses influencing ETE in PTC

The univariate analysis results revealed that age <45 years, tumor located at the isthmus, tumor diameter ≥8 mm, multifocal, and LNM were significantly associated with a higher likelihood of ETE (all P<0.05). Further multivariate logistic regression analysis of the statistically significant variables from the univariate analysis indicated that age <45 years, tumor located at the isthmus, tumor diameter ≥8 mm and LNM were independent risk factors for ETE (all P<0.05), as shown in Table 7.

PSM and analysis

After matching age, tumor side and tumor size, our cohort included 642 patients with 321 patients in each group. Table 8 shows the characteristics of each group. After matching, there were no significant difference in the clinicopathological features between the two groups. Further binary logistic regression analysis revealed no significant relationship between LNM and ETE (P>0.05) (Table 9).

Discussion

TC is the cancer with the highest proportion in the endocrine system, and its incidence has increased the fastest among all malignant tumors in the world in recent decades (15,16). PTC accounts for about 95% of all TC, in which there is a trend of early metastasis. LNM is reported to range from 20% to 90% at the time of diagnosis (3,17,18). Although LNM does not affect the overall prognosis of patients, it is an important feature of PTC with invasiveness and a major predictor of disease-free survival (19). In addition, there are potential risks of neurological and parathyroid dysfunction in central lymph node dissection (20). Therefore, the range of accurate lymph node dissection is very important, and the key is to identify the risk factors of LNM (21).

Consistent with the findings of most studies (22-25), our study found that male, age <45 years, multifocal, and tumor size ≥8 mm were independent risk factors for LNM in PTC. Notably, the median tumor size in our cohort was 8.0 mm, with 48.1% of patients presenting with tumors ≤8 mm, placing them within the subcentimeter PTC category. This subgroup is increasingly detected in clinical practice, yet remains challenging to stratify due to limitations in preoperative imaging and cytology (26-29). Our findings therefore provide relevant evidence for risk assessment in these small carcinomas, particularly in determining whether ETE should influence the decision for prophylactic lymph node dissection.

Although many studies have shown that the combination of ETE is a risk factor for LNM, for example, the study by Wen et al. (30) showed that ETE was a reliable predictor of PTC LNM (OR: 1.96), Liu et al. (31) found that ETE was an independent risk factor for LNM in the central area (OR: 1.68).

However, there are still some studies do not find the correlation between PTC LNM and ETE through the analysis of them. For example, the LNM prediction model published by Chen et al. (11) in 2024 did not mention the correlation between ETE and LNM. In this study, after eliminating intergroup differences and selection bias by using PSM, we found that the relationship between ETE and LNM may not be significant.

To further investigate the correlation between ETE and LNM, this study explores the identification of risk factors for ETE. We found that age <45 years, tumor located at the isthmus, tumor diameter ≥8 mm and LNM were independent risk factors for ETE. Younger patients were more likely to develop ETE. Anatomically, the isthmus is a smaller central area connecting the two lobes of the thyroid. The larger the tumor diameter is, the higher the probability of ETE occurrence. In PSM analysis, we found no significant correlation between LNM and ETE, which further validates the relationship between the two factors.

Why did minimal ETE appear to be an independent risk factor in the multivariate model but not after PSM? We hypothesize that this discrepancy reflects residual confounding in the original cohort. Minimal ETE was significantly more common in patients with larger tumors (≥8 mm), younger age (<45 years), and multifocal disease—each of which is an established risk factor for LNM. Although multivariate logistic regression adjusts for these covariates, it cannot fully account for non-linear interactions or imbalance in covariate distributions across exposure groups. PSM, by creating balanced cohorts with near-identical distributions of observed confounders, effectively removes these sources of bias. The disappearance of the association post-matching implies that minimal ETE is likely a marker of nodal metastasis, rather than a mechanistic contributor.

Although ETE has long been considered a marker of tumor aggressiveness in PTC, our study—using PSM to reduce selection bias—found no significant association between ETE and LNM. This finding aligns with a growing body of molecular evidence suggesting that local invasion and metastatic potential are biologically decoupled processes. Local invasiveness does not directly equate to metastatic potential. ETE only reflects the ability of cancer cells to breach the basement membrane, a process that depends on the activity of local proteases. However, LNM involves several complex steps, including migration, infiltration of lymphatic vessels and distant colonization. Therefore, the occurrence of LNM is much more complex than local invasiveness (32,33).

Pu et al. (34) analyzed 158,577 cells’ transcriptome information from 11 PTC patients and found heterogeneity between LNM and distant metastatic PTC cells. On the other hand, Vander Heiden et al. suggested that the invading cancer cells may be mainly invasive clones, while metastatic clones may be unable to effectively recognize lymphatic signals due to metabolic requirements or insufficient expression of chemokine receptors (such as CCR7) (35,36). In addition, the connective tissue outside the thyroid capsule is dense and lacks extracellular matrix components that promote metastasis, which hinders the spread of cancer cells to the lymphatic vessels and limits LNM (37,38).

Tumor immune microenvironment also plays an important role in the occurrence of LNM. Capsule destruction may release damage-associated molecular patterns (DAMPs), recruit macrophages, etc., enhance local immune surveillance and remove cancer cells from the primary focus (39). TNF-α and IFN-γ in microenvironment may inhibit epithelial-mesenchymal transformation (EMT) or induce apoptosis, and reduce the efficiency of metastasis (40). Recent multi-omics analyses have identified LY75 and S100A12 as key regulators of PTC progression, influencing immune evasion and nodal involvement independent of anatomical extension (41). Similarly, p53 immunocytochemical expression in thyroid fine-needle aspiration samples has been shown to correlate with aggressive histological features and LNM, even in the absence of ETE (42), suggesting that molecular dysregulation may precede and predict metastatic behavior more accurately than structural invasion.

Further support comes from the BRAF V600E-AXL-PD-L1 signaling axis, which has been implicated in promoting immune escape, reducing NIS expression, and facilitating LNM in intermediate-risk PTC, independent of ETE status (43). Notably, a recent comprehensive review on anaplastic thyroid carcinoma (ATC) highlights that stepwise molecular evolution, starting with MAPK pathway activation (e.g., BRAF V600E), and progressing through additional alterations such as TP53 loss, TERT promoter mutations, and PI3K/AKT activation, underlies the transition from well-differentiated tumors to aggressive phenotypes (44). Importantly, these molecular events drive dedifferentiation, immune evasion, and metastatic spread, even when structural features like ETE are minimal or absent.

Collectively, these data support a molecularly driven model of metastasis, where genomic and immune microenvironmental factors outweigh traditional histopathological features such as ETE in determining LNM risk. Therefore, relying solely on ETE to guide the extent of lymph node dissection may result in overtreatment or underestimation of metastatic potential. Future risk stratification strategies should incorporate molecular profiling, immune markers, and genomic classifiers to refine surgical planning and personalize treatment approaches in PTC.

Our study used the PSM method to balance age, sex, tumor side, tumor size, and multifocal. Therefore, when comparing the effects of different degrees of ETE on LNM, we can reduce the selection bias and provide valuable reference data for the risk assessment of LNM in PTC patients.

Our study is not without its limitations. The PS is generated based on available covariates, but this does not eliminate the possible bias created by unmeasured cofounders. PS does not necessarily provide superior results to multivariate outcome regression models, but it does allow a straightforward assessment of whether the treated and control groups are comparable after applying the PS and allows a separation of modeling and outcome analysis. On the other hand, the data collected in this study is from a single institution, which may involve various biases, including selection bias. Moreover, due to the limited number of cases available for collection, the sample size included in the study is limited. Although the matched samples were smaller, the number of outcome events remained more than 10 times the number of covariates, satisfying minimal power requirements for logistic regression; nevertheless, we conservatively interpret the non-significant result as “no observed association” rather than “proof of no association”, future multicenter randomized clinical trials can improve the level of scientific evidence for these conclusions. Therefore, the conclusion of this study needs to be further verified by a multicenter prospective study involving more patients, in order to obtain more accurate and rigorous results.

Conclusions

In this single-center, PSM-retrospective cohort, we did not observe a significant association between the degree of ETE and LNM. Pending external validation, clinicians are advised to tailor the extent of lymph-node dissection in ETE-positive patients, carefully weighing oncological benefit against surgical morbidity.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-319/rc

Data Sharing Statement: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-319/dss

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-319/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-319/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by the Ethics Committee of the First Affiliated Hospital of Chongqing Medical University (No. 2025-169-01) and informed consent was waived because there was no patient interest or privacy breach in the form of disclosure of personal information.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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