The prognostic value of central excised lymph node count in N1a papillary thyroid cancer: a population-based study

Introduction

In the past few decades, the overall incidence of thyroid cancer has increased at a rate of approximately 3% per year, largely attributable to a rise in papillary thyroid cancer (PTC) (1,2). PTC constitutes the majority of well-differentiated thyroid cancers and is generally considered an indolent tumor, with a 10-year survival of about 93% (1,3). PTC is known for its tendency to metastasize to lymph nodes, initially affecting the central compartment before spreading to the lateral compartment (4,5). The presence of lymph node metastases is a significant prognostic factor for PTC, representing a major risk for high recurrence rates and diminished survival outcomes among patients (6-11).

Approximately half of patients with PTC present with metastatic lymph nodes at the time of diagnosis (12,13). Therapeutic central-compartment dissection is widely recognized as an essential treatment for patients with clinically involved central nodes (14,15). Conversely, prophylactic central-compartment dissection may be considered for patients with specific prognostic factors indicative of increased risk for metastasis and recurrence, such as larger tumor size, multifocal disease, extrathyroidal extension, and known lateral node metastases (14,16,17). Preoperative neck ultrasound is the preferred imaging modality for evaluating cervical lymph nodes, crucial for determining the extent of surgery, especially for lymph node dissection (14). However, due to the obstruction caused by the thyroid gland, bones, or gas pockets, preoperative ultrasound detects only about half of the lymph nodes identified during the surgical procedure (13).

In gastrointestinal and breast cancers, the link between a higher number of excised lymph nodes (ELNs) and improved patient survival is well established, with the National Comprehensive Cancer Network (NCCN) guidelines recommending a minimum number of ELNs for adequate nodal staging (18-20). Similarly, different ELN counts have been suggested for various lymph node fields in staging cutaneous melanoma and for evaluating postoperative quality of lymph node examination or prognosis in non-small-cell lung cancer, where 16 ELNs is a recommended threshold (21,22). For PTC, evidence indicates that an increasing number of metastatic lymph nodes, up to six, correlates with higher mortality risk for patients younger than 45 years (23). Nevertheless, the optimal number of lymph nodes to excise during central neck dissection in PTC remains undefined.

To address this unresolved issue, we analyzed a large cohort of N1a PTC patients from the Surveillance, Epidemiology, and End Results (SEER) database. Restricted cubic splines (RCSs) based on a multivariable Cox model was a well-validated approach for modeling nonlinear survival relationships. In this study, we employed RCSs and multivariate Cox proportional hazards regression models to explore the associations between central ELN count and overall survival (OS). Additionally, sensitivity analyses were performed to assess the robustness of our findings. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0240/rc).

Methods

Study population

We retrieved data from the SEER Database (SEER*Stat version 8.4.1), which covers approximately 28% of the US population. This population-based research tool provides comprehensive information on the clinical management of cancer patients. Using the International Classification of Diseases for Oncology, Third Edition (ICD-O-3), we identified patients with pathologically confirmed N1a PTC (codes 8050/3, 8260/3, 8340/3–8343/3) as their first primary malignancy diagnosed between 2004 and 2015. Exclusions comprised patients with unknown surgical status, those undergoing lateral neck dissection (levels I–V), those with distant metastases, and those with aggressive histologic variants (tall cell, columnar cell, diffuse sclerosing, and insular subtypes; ICD-O-3 codes 8344, 8337, and 8350), given their distinct biology and poorer prognosis.

The distribution of ELN numbers in the selected patients was skewed with extreme values (Figure 1). To minimize the influence of outliers, individuals in the top 10% of the ELN distribution (i.e., >20 ELNs) were excluded. Ultimately, the final cohort comprised 10,445 patients, and the patient selection flowchart is shown in Figure 2. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Figure 1 Distribution of the number of central ELNs in the entire cohort. ELN, excised lymph node.

Figure 2 Flowchart of sample selection (N=10,445). ELN, excised lymph node; PTC, papillary thyroid cancer; SEER, Surveillance, Epidemiology, and End Results.

Statistical analyses

The covariates included age, sex, race (white black, or other), extent of surgery (lobectomy or total thyroidectomy), radioactive iodine treatment (yes or no), extrathyroidal extension, tumor size (≤2 cm, >2 cm to ≤4 cm, and >4 cm), American Joint Committee on Cancer (AJCC) staging, tumor (T) (T1, T2, T3, or T4) and the number of positive lymph nodes. Continuous data are presented as mean ± standard deviation (SD) or median [interquartile range (IQR) or range], while categorical data are expressed as n (%). Baseline data and clinicopathological characteristics were compared using Pearson’s Chi-squared test for categorical variables and t-tests or Wilcoxon rank-sum test for continuous variables, based on the type and distribution of the data.

RCS models with four knots positioned at the 5th, 35th, 65th, and 95th percentiles were used to flexibly model the relationship between ELN count and OS, with hazard ratios (HRs) calculated. Multivariate Cox proportional hazards regression models were used to estimate HR and 95% confidence interval (CI) and to assess the associations between the number of ELNs and OS, adjusting for potential covariates. Given the identified nonlinear relationship, two-piecewise Cox models were fitted around the identified inflection point to estimate HRs separately for ELN counts below and above the threshold.

Sensitivity analyses were conducted by excluding patients with shorter survival times to validate the association between the ELN number and OS. All statistical analyses were performed using SPSS (version 27, IBM Corporation, Armonk, New York, USA) and R language (Version 4.4.0) in the RStudio environment (Version 2023.12.1+402) with a significance level set at a two-sided P value of less than 0.05.

Results

Baseline characteristics

In this study, a total of 10,445 eligible PTC patients were ultimately enrolled, and the baseline characteristics are detailed in Table 1. The cohort was predominantly female and White, with most patients undergoing total thyroidectomy and receiving radioactive iodine therapy. Tumor size was ≤2 cm in the majority of cases. Over a median follow-up time of 94 months (range from 0 to 191 months), 510 deaths were recorded. The median central ELN count was 5 (IQR, 2–9).

Number of ELNs and survival

Multivariable Cox models incorporating RCSs revealed a nonlinear, L-shaped relationship between ELN count and OS (Figure 3; P for nonlinearity <0.05). Mortality risk declined with increasing ELN yield up to a nadir at 5 ELNs, beyond which the curve plateaued. After adjusting for various factors, each additional ELN below the threshold was associated with a 15% lower risk of all-cause mortality (HR, 0.85; 95% CI: 0.76–0.95), whereas no significant association was observed for ELN counts exceeding 5 (HR, 1.00; 95% CI: 0.97–1.04; Table 2).

Figure 3 Association of ELN count with overall survival in the entire cohort. HRs are indicated by solid lines and 95% CI by shaded areas. Knots placed at 5th, 35th, 65th, and 95th centiles of excised lymph node count distribution. Model was adjusted for age, sex, race, extent of surgery, radioactive iodine treatment, extrathyroidal extension, tumor size, AJCC T staging and the number of positive lymph nodes. The vertical dashed line represents the inflection point estimated by the curve. AJCC, American Joint Committee on Cancer; CI, confidence interval; ELN, excised lymph node; HR, hazard ratio; T, tumor.

Sensitivity analyses

After excluding patients with survival times below the 10th percentile, the L-shaped pattern persisted (Figure S1), and HR estimates remained consistent: 0.85 (95% CI: 0.74–0.98) for ELN ≤5 and 0.99 (95% CI: 0.94–1.05) for ELN >5, supporting the robustness of the primary findings against potential immortal time bias (Table S1).

Discussion

To our knowledge, this is the first study to characterize the nonlinear relationship between central ELN count and OS specifically in patients with N1a PTC. Using RCS, a method that does not presuppose linearity, we identified an L-shaped association with a threshold at 5 ELNs. Below this point, incremental node resection was associated with progressively improved survival; above it, no further benefit was evident. These findings suggest that ELN yield may serve as a quality indicator for central compartment dissection in this patient population, offering a potential benchmark for evaluating surgical adequacy.

Several mechanisms may underpin the observed association. Firstly, a lower ELN count may reflect incomplete nodal staging, potentially leaving undetected metastases that could compromise long-term outcomes. Conversely, more thorough nodal clearance may reduce the burden of residual disease, thereby lowering recurrence risk (24). Secondly, the absence of additional benefit beyond 5 ELNs may indicate that once adequate sampling is achieved, further dissection does not meaningfully alter staging or therapeutic decision-making. This plateau effect is consistent with the concept of diminishing returns in surgical staging, where a minimum threshold is necessary for accurate prognostication, but additional nodal harvest beyond that point does not translate into further survival advantage.

Approximately half of patients with PTC present with metastatic lymph nodes at the time of diagnosis (13). Although preoperative ultrasonography remains the standard for nodal assessment, its sensitivity is suboptimal, and other imaging modalities offer limited additional accuracy (13,14,25-27). Consequently, the true extent of nodal involvement may be underestimated preoperatively. Inadequate surgical staging due to occult lymph node metastases may necessitate reoperation, increasing surgical risks like recurrent laryngeal nerve injury and hypoparathyroidism (28,29). Thus, achieving an appropriate lymph node yield during the primary surgery is critical for balancing oncologic completeness with surgical safety.

Our results should not be interpreted as endorsing the routine removal of only five lymph nodes or advocating for prophylactic central dissection in all PTC patients. Critically, central neck dissection should always be performed as a systematic, en bloc clearance of the level VI fibrofatty tissue rather than as selective “cherry-picking” of individual nodes. Surgeons do not count lymph nodes intraoperatively; the ELN count is determined postoperatively by pathological examination. Rather, they provide a reference point for clinicians and patients to contextualize the potential prognostic value of ELN yield and to inform discussions regarding the extent of dissection in individual cases. The proposed threshold of 5 ELNs should be viewed as a quality metric or benchmarking tool, a minimum target for adequate nodal staging, rather than a strict surgical goal. If a postoperative pathology report in a patient with N1a disease reveals fewer than 5 central lymph nodes, this may prompt consideration of whether the surgical dissection was sufficiently thorough, whether pathological specimen examination was adequately detailed, or whether the patient may have been understaged.

Several limitations merit consideration. First, it is inherently constrained by the nature of retrospective analyses. Although we adjusted for available covariates, the possibility of unmeasured confounding remains. Second, the SEER database lacks data on the extent of nodal involvement (e.g., metastasis size, extranodal extension) and recurrence events. These factors are known to influence prognosis and may affect the observed association. The lack of data on autoimmune thyroiditis, which may cause reactive lymph node hyperplasia and potentially inflate ELN counts. We were therefore unable to adjust for this potential confounder, and future studies with detailed pathological data are needed to clarify its impact. Third, the specific intent of central-compartment lymph node dissection (whether therapeutic or prophylactic) for the patients in our study is unknown. Fourth, some deaths may be unrelated to PTC, potentially introducing bias. The inability to confirm PTC-specific mortality represents a significant limitation, and future studies incorporating cause-of-death adjudication and recurrence endpoints are needed to validate our findings. Fifth, unmeasured factors such as surgeon experience and institutional practices may influence both ELN counts and outcomes. Variations in surgical technique and pathological examination protocols across institutions could contribute to heterogeneity in ELN yields. The treatment patterns observed in our study differ from current recommendations, as the study period [2004–2015] considerably predates the publication of the contemporary American Thyroid Association (ATA) guidelines. Finally, the optimal ELN threshold for clinically N0 patients remains to be defined. Future prospective studies that incorporate detailed clinicopathologic data and distinguish between dissection types are needed to validate and extend these findings, ideally with inclusion of disease-specific survival and recurrence endpoints.

Conclusions

In this large retrospective cohort of patients with N1a PTC, central ELN count exhibited an L-shaped association with OS, with a threshold effect at 5 ELNs. These findings support the role of ELN yield as a prognostic indicator and suggest that resecting more than five central lymph nodes may not confer additional survival benefit. Prospective validation is required to address inherent biases and to further define the role of ELN count in surgical quality assessment and treatment planning.

Acknowledgments

We thank the SEER program for approving our protocol and providing the custom datasets.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0240/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0240/prf

Funding: The work was supported by the Natural Science Foundation of Tianjin (No. 25JCYBJC00280).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2026-0240/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.

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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