Metastasis number and ratio in regional lymph nodes as predictive indicators for distant metastasis in medullary thyroid cancer: beyond American Joint Committee on Cancer nodal staging

Introduction

Medullary thyroid cancer (MTC) is a neuroendocrine tumor that arises from parafollicular C cells of the thyroid gland. It represents less than 5% of all thyroid malignancies, but results in 13–14% of all thyroid cancer-related deaths (1-3). The only curative treatment of MTC is total thyroidectomy and lymph node dissection. Calcitonin (Ctn) plays an important role in the recognition of MTC, whether the tumor is large or small, primary or recurrent, and it can also predict therapy response as well as prognosis in some extent (4,5). Although the assessment of Ctn is crucial in the diagnostic workup of MTC, more comprehensive evaluations are necessary, because serum Ctn levels are influenced by anthropometric and pharmacological determinants (6). Distant metastasis is a poor prognostic factor which can potentially predict overall rate and disease-specific death for patients with MTC (7,8). The 8th edition of the American Joint Committee on Cancer (AJCC) tumor-node-metastasis (TNM) staging system for MTC, implemented in 2018, showed N stage based on the location of these lymph nodes inside or outside the central neck, without considering the number of affected lymph nodes (9). Recent studies have shown a correlation between a greater number of lymph nodes and poorer prognosis in patients with MTC, emphasizing the importance of lymph node count (10). Not only the number of lymph node metastasis, but also the ratio of positive lymph nodes to the examined ones is an important prognostic factor for MTC (11). Positive regional lymph node ratio, which reflects the extent of local metastasis and the quality of lymph node dissection can predict the risk of distant metastasis in patients undergoing thyroidectomy and lymph node dissection (12). Some potential risk factors for distant metastasis, including the age of diagnosis, tumor diameter, extrathyroidal extension and lymph node metastasis, are crucial determinants of cancer-specific survival (13-15).

Distant metastases in MTC often occur in the lungs, liver, and bones, and the presence of distant metastasis is a poor prognostic indicator for long-term survival (16). Metastases to the lungs and liver have been reported as common occurrence (17,18). The number of involved lymph nodes has been proved to be an effective predictor for lung metastasis in patients with MTC (19). Bone metastasis can also be frequent in the dissemination of MTC (20). Patients with MTC face a significant risk of experiencing skeletal complications, with bone events serving as strong indicators of poor prognosis (21). Nevertheless, previous studies have frequently failed to distinguish characteristics according to the location of distant metastasis, mainly because of the scarcity of MTC. This study aimed to estimate the risk of distant metastasis in patients with MTC through the number and ratio of positive regional lymph nodes. We present this article in accordance with the STROBE reporting checklist (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-378/rc).

Methods

Study population and design

This study was based on the Surveillance Epidemiology and End Results (SEER) STAT 8.4.3 database, with the “primary site label” variable set to C73.9. The histology of the tumor tissue was classified according to the International Classification of Diseases for Oncology, 3rd edition (ICD-O-3) codes as MTC (8345/3, 8510/3). The data of patients diagnosed with MTC from 2018 to 2022 were extracted. To compare the clinical characteristics of patients with and without distant metastasis, as well as the predictive results of distant metastasis based on positive regional lymph nodes and the 8th edition of the AJCC N stage, patients with unclear distant metastasis status were excluded. Ultimately, 744 eligible patients were included in the statistical analysis.

The demographic variables included age, gender, and race at the time of diagnosis. Clinical and pathological features included tumor diameter, number of regional lymph nodes involved, and distant metastasis, according to the information from “Tumor Size Summary (2016+)”, “Regional nodes positive (1988+)”, “Regional nodes examined (1988+)”, and “SEER Combined Mets (2010+)”. The tumor stage and survival status were selected and classified using “Derived EOD 2018 (2018+)”, “Vital status recode” and “SEER cause-specific death classification”. The largest primary tumor diameter was categorized as ≤20, 21–40, and >40 mm. The number of positive regional lymph nodes were categorized as 0, 1–10, 11–20, and >20 lymph nodes. Lymph node ratio defined as the ratio of positive lymph nodes to the examined ones. All patients in the study were classified according to the 8th edition of the AJCC TNM staging system. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments.

Statistical analysis

To identify the cut-off value of positive regional lymph node ratio that best predicted distant metastasis, receiver operating characteristic (ROC) curve analysis was performed and the area under the curve was calculated. The cut-off value was determined to optimize the combination of sensitivity and specificity calculated from the analysis of the ROC curve. Odds ratios (ORs) with 95% confidence intervals (CIs) were presented to indicate the difference in outcomes. Pearson’s chi-square test was used to compare variables between patients with and without distant metastatic lesions. Multivariate logistic regression was performed to determine the predictive value of the number and ratio of regional lymph nodes involved for identifying distant metastasis, compared with the AJCC 8th N stage. Besides the factor of the condition of regional lymph nodes, the model of multivariate logistic regression included the factors of the age of diagnosis, gender and tumor size. Kaplan-Meier analysis was conducted to explore the relationship between positive regional lymph nodes and distant metastasis. All the statistical analyses in this study were conducted using R software (version 4.3.2). P<0.05 was considered statistically significant.

Results

Clinical characteristics of patients with MTC

The baseline characteristics of the entire cohort are shown in Table 1. Among the 744 patients with MTC, nearly a half were 60 years old or over (47.0%). There were slightly more female patients (57.5%) than male patients (42.5%). White people made up the majority (81.9%). In the entire cohort, 706 patients (94.9%) were not found any distant metastasis, with nearly a half of them having a tumor diameter not greater than 20 mm, no regional lymph node involvement, and an AJCC 8th stage of T1 or N0. Most patients were alive during follow-up, with 43 patients (5.8%) experiencing death as their outcome.

However, the other 38 patients with distant metastasis displayed different features. Although there is no significant difference in age, gender, and race between patients with one distant organ system involvement and those without distant metastasis, patients with one distant organ system metastasis presented with significantly larger primary tumor diameter and more frequently lymph node involvement. When distant metastasis occurred, the mortality rate could even increase to a quarter or even close to half. There were also 11 patients with distant metastasis of 2 organ systems or over. Compared with patients with only one affected organ system, no significant differences were found in terms of demographic characteristics as well as tumor features. According to the univariate analysis, patients with distant metastasis were more likely to be with larger tumor diameters, more affected lymph nodes, and higher mortality rates.

Comparisons of multivariate analysis of distant metastasis by the AJCC 8th N category and the number of positive regional lymph nodes

Multivariate logistic regression analysis was applied to evaluate the risk factors for distant metastasis (Table 2). The number of affected regional lymph nodes were found to play crucial roles in predicting distant metastasis. As for the numeric lymph node categories, the number of positive regional lymph nodes could predict the risk of distant metastasis (Table 2, analysis 1), with 1–10 (OR 9.13; 95% CI: 2.47–59.11; P=0.004), 11–20 (OR 25.72; 95% CI: 6.52–171.29; P<0.001), and >20 (OR 26.44; 95% CI: 6.50–178.95; P<0.001) metastatic regional lymph nodes, compared with no metastasis of regional lymph nodes, denoting risk in an upward trend. In this model, primary tumor diameter also entailed a great risk of distant metastasis, with 21–40 mm (OR 2.74; 95% CI: 1.05–8.00; P=0.045), and >40 mm (OR 6.88; 95% CI: 2.70–19.93; P<0.001), compared with the tumor diameter not exceeding 20 mm. The 8th edition of the AJCC N stage also could predict the risk of distant metastasis (Table 2, analysis 2), with N1a (OR 6.21; 95% CI: 1.46–42.42; P=0.03), and N1b (OR 23.20; 95% CI: 6.69–146.54; P<0.001), compared with the stage of N0, but the upward trend was relatively slower than the number of metastatic regional lymph nodes. Primary tumor diameter also showed a great risk of distant metastasis in the model based on the 8th edition of the AJCC N stage.

The types of distant metastases included bone, liver and lung metastasis. According to the 8th edition of the AJCC TNM staging system, a significant relationship could be found between the N1b stage and bone metastasis in patients with MTC (OR 7.75; 95% CI: 1.97–51.57; P=0.01), compared to the N0 stage, but the N1a stage was not significantly associated with the risk of bone metastasis (Table 3, analysis 2). An upward trend could be found in the model based on the number of affected regional lymph nodes in predicting bone metastasis. Compared with no metastatic regional lymph nodes, 11–20 affected lymph nodes denoted moderate risk (OR 8.19; 95% CI: 1.50–61.69; P=0.02), and more than 20 affected lymph nodes indicated high risk (OR 12.91; 95% CI: 2.59–95.99; P=0.004) (Table 3, analysis 1). As for other types of distant metastases, since patients with liver metastasis and lung metastasis were all involved with regional lymph node metastasis, we could not find significant differences in the models based on both the number of affected regional lymph nodes and the 8th edition of the AJCC N stage (Tables S1,S2). Nevertheless, based on the number of metastatic regional lymph nodes, primary tumor diameters over 40mm entailed great risks of both liver (OR 3.67; 95% CI: 1.22–12.42; P=0.02) and lung metastasis (OR 20.79; 95% CI: 3.79–388.08; P=0.02), compared with the tumor diameter not exceeding 20 mm, and similar results could be seen in the model based on the 8th edition of the AJCC N stage, with liver metastasis (OR 3.73; 95% CI: 1.24–12.61; P=0.02) and lung metastasis (OR 20.56; 95% CI: 3.76–383.35; P=0.005).

Cut-off value of the ratio of metastatic regional lymph nodes

Metastatic regional lymph node ratio was a reliable determinant of distant metastasis. The cut-off value of metastatic regional lymph nodes in predicting distant metastasis was 0.176 by ROC curve analysis with sensitivity 92.1% and specificity 66.0% (Figure 1A). The cut-off value of metastatic regional lymph nodes in predicting bone, liver and lung metastasis were 0.317, 0.372 and 0.176, separately (Figure 1B-1D). Distant metastasis occurred in only 0.6% of patients with the ratio of metastatic regional lymph nodes less than 0.176. Patients with the ratio greater than cut-off value were found to have a significantly higher risk of developing distant metastasis (OR 18.24; 95% CI: 6.33–77.26; P<0.001), and similar results could be seen in the prediction of bone metastasis (OR 21.25; 95% CI: 5.72–138.23; P<0.001) (Table 4), and liver metastasis (OR 14.53; 95% CI: 4.53–64.99; P<0.001) (Table S3). However, we could not find significant differences in the prediction of lung metastasis using the factor of ratio of metastatic regional lymph nodes (Table S3). We could also find significance of predicting liver (OR 3.85; 95% CI: 1.27–13.12; P=0.02) and lung metastasis (OR 22.60; 95% CI: 4.08–423.83; P=0.004) by primary tumor diameters over 40 mm, compared with the tumor diameter not exceeding 20 mm (Table S3). The cumulative rates of bone, liver, and lung metastasis were plotted against the number of positive lymph nodes (Figure 2) and lymph node ratio (Figure 3). Regardless of whether patients were involved with or without concurrent metastasis of distant organs, the plots for bone, liver, and lung metastasis showed remarkable similarity, indicating that both the number and the ratio of positive lymph nodes can effectively reflect the overall risk of distant metastasis.

Figure 1 Lymph node ratio ROC curve considering patients with MTC. (A) Distant metastasis. (B) Bone metastasis. (C) Liver metastasis. (D) Lung metastasis. AUC, area under the curve; MTC, medullary thyroid cancer; ROC, receiver operating characteristic.

Figure 2 Cumulative rates of distant metastasis by the number of positive regional lymph nodes. (A) Patients with distant metastasis. (B) Each distant organ system involved separately.

Figure 3 Cumulative rates of distant metastasis by lymph node ratio. (A) Patients with distant metastasis. (B) Each distant organ system involved separately.

Discussion

This study quantified the independent contribution of positive regional lymph nodes to distant metastasis in patients with MTC via a multivariate logistic regression model. Both the number of metastatic lymph nodes and the ratio of metastatic lymph nodes to total number of retrieved lymph nodes can be better indicators of evaluating distant metastasis than the 8th edition of the AJCC N stage.

There is still a lack of consensus on the minimum number or ratio of lymph nodes required for reliable prediction of MTC progression. Machens and Dralle determined that the number of metastatic lymph nodes was a key factor in the analyses of distant metastasis and survival conditions (19). The number of affected regional lymph nodes is an effective predictor of local recurrence risk and cancer-specific mortality, with the risk of local recurrence associated with the number of cleared lymph nodes during initial surgery. Scollo et al. reported that patients with MTC were more susceptible to invasion of regional lymph nodes, which were more common in those with larger tumors (22). It has been reported that more extensive surgery may not result in improved survival, suggesting that the benefits of removing a large quantity of lymph nodes are limited and primarily influenced by other factors (23). The lymph node ratio, defined as the ratio of lymph nodes with tumor metastasis to the total lymph nodes dissected, was proposed as a prognostic factor for MTC (11). Prinzi et al. reported a strong link between a high lymph node ratio and factors such as larger tumor diameter, increased levels of Ctn, and a higher chance of developing distant metastasis during follow-up (12). Deandrea et al. emphasized the importance of preoperative neck ultrasound that an elevated lymph node ratio may result either from a lower number of lymph nodes harvested during surgery or from insufficiently radical surgery due to inadequate preoperative planning (24). Chen et al. proposed an MTC-specific N staging system based on the number of metastatic lymph nodes and the lymph node ratio to better predict survival, thereby improving patient outcomes and more accurately identifying patients in need of further treatment and close monitoring (10). Wang et al. improved the 8th edition of the AJCC N stage based on the location and count of lymph nodes to optimize the clinical diagnosis and treatment process (25). Shen et al. proposed adjustments to the N category by integrating the lymph node metastasis at the site of upper mediastinum into TNM staging system to improve the applicability for patients with MTC (26). The modification of the 8th edition of the AJCC classification may have clear advantages of greater risk stratification and easier recognition of those who may benefit from additional adjuvant therapy including radiotherapy and possibly also targeted therapy in the future.

As for different types of distant metastases, this study also suggested that the number of metastatic lymph nodes can serve as predictive factors for the likelihood of bone metastasis, and the ratio of metastatic lymph nodes can predict the risk of both bone metastasis and liver metastasis. The occurrence of bone metastasis often significantly impacts quality of life, as it leads to skeletal-related events such as pain, pathological fractures, spinal cord compression, and hypercalcemia (27). The presence of bone metastasis with osteolytic morphology in patients with MTC usually suggests poor prognosis (28). Zhang et al. noted that older age, male gender, black race, larger tumor diameter, and lymph node metastasis were significantly associated with bone metastasis in patients with thyroid cancer, with MTC greatly increasing the risk of bone metastasis (29). Liver metastasis in thyroid cancer is rare but fatal. Xu et al. indicated that age, histology, AJCC T stage and lymph node metastasis were the independent risk factors for liver metastasis in patients with thyroid cancer, with MTC exhibiting the highest risk of metastasis (30). Given the specific management of different metastatic lesions, future research exploring factors that can effectively predict more types of distant metastases will be essential.

There are several limitations in this study. Firstly, this cross-sectional study, based on the SEER database, only provides information on the presence of distant metastasis at the time of diagnosis in patients with MTC, but cannot analyse the potential incidence of distant metastasis during the disease course. On top of this, other histological features, such as proliferation and necrosis, may also have an impact on prognosis, but neither TNM staging nor the number or ratio of affected lymph nodes have included hints of histological characteristics. Moreover, the result of this study can show its value for those patients who have clinical evidence of metastatic regional lymph nodes, but it may have less applicability in those who only need less extensive surgery that enable sparing the neck. Additionally, due to the slow rate of progression for many patients, the appropriate measure of outcome may be 5- or 10-year survival, but it cannot be assessed with only 4-year duration of follow-up in this study.

Conclusions

In conclusion, the number and ratio of metastatic regional lymph nodes can effectively predict the risk of distant metastasis in patients with MTC, outperforming the 8th edition of the AJCC N stage. Further investigations are necessary to confirm and even propose revised staging classifications to help predict distant metastasis and prognostic survival in patients with MTC.

Acknowledgments

The authors extend appreciation to the staff and participants of the SEER database for their valuable contributions.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-378/rc

Peer Review File: Available at https://gs.amegroups.com/article/view/10.21037/gs-2025-378/prf

Funding: This work was supported by the Preferred Research Foundation for the Returned Overseas Scholars from Ministry of Human Resources and Social Security of China (Key Category) (2014) and Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences (No. 2021-I2M-1-001).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://gs.amegroups.com/article/view/10.21037/gs-2025-378/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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