Risk factors for postoperative recurrence of thyroid cancer patients in children, adolescents, and young adults

Introduction

Papillary thyroid carcinoma (PTC) is the most prevalent endocrine malignancy in pediatric and adolescent patients, accounting for approximately 10% of all pediatric cancers (1). Compared with adult patients, pediatric and adolescent PTC cases are associated with a more favorable prognosis, yet the incidence of pediatric thyroid cancer continues to rise rapidly worldwide (2,3). While advances in diagnostic imaging have facilitated the detection of early-stage thyroid lesions (4), this improved diagnostic capability does not account for the genuine rise in thyroid cancer incidence among adolescents and young adults, which is likely driven by factors such as obesity (5,6). More notably, driven by genetic profile differences, tumors in younger patients exhibit anatomical features such as high vascularization and thin capsule; coupled with the tumor-promoting effect of developing thyroid tissue, these factors collectively render younger patients with PTC more prone to presenting with aggressive, advanced-stage disease (7,8).

To date, clinical treatment guidelines for adult thyroid cancer are well-established (9), whereas the American Thyroid Association Guidelines Task Force did not release the first dedicated guidelines for thyroid nodules and differentiated thyroid cancer in pediatric and adolescent patients under 18 years of age until 2015 (10). For adult patients, thyroid cancer management remains centered on surgery, supplemented by radioactive iodine therapy and endocrine therapy; although standard treatment has improved the long-term survival rate of most PTC patients, these adult-focused guidelines may not be applicable to younger populations. Treating younger patients with adult-oriented protocols or prioritizing cure rates blindly poses an often-overlooked risk of long-term harm caused by overtreatment. While radioactive iodine-131 therapy theoretically yields favorable prognostic outcomes and prolonged survival for these patients, it also elevates the risk of adverse complications. Published studies have confirmed that late sequelae of such radiation therapy include infertility, pulmonary lesions, and secondary malignancies (10,11). Conversely, conservative treatment strategies carry inherent risks of disease recurrence and the need for reoperation. Therefore, accurate risk stratification is essential for this patient population to guide the selection of optimal therapeutic regimens, thereby mitigating the risks of both undertreatment and overtreatment. The present study aims to investigate the impact of clinicopathological characteristics on postoperative recurrence in young thyroid cancer patients, with the goal of preventing both therapeutic delays and unnecessary overtreatment. We present this article in accordance with the STROBE reporting checklist (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-1-871/rc).

Methods

Patients

We reviewed all patients with thyroid carcinoma who underwent operation treatment at Tianjin Medical University Cancer Institute and Hospital (Tianjin Cancer Hospital) between January 2012 to January 2019, the study ensured that we had access to detailed information of all the patients and there was sufficient follow-up time. A total of 234 patients ≤25 years, regarded as children, adolescents, and young adults (CAYAs) (12-14), and 311 patients >25 years, with thyroid cancer were selected. The present study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments and was approved by the Medical Ethics Committee of Tianjin Cancer Hospital (No. bc20240001) and informed consent was taken from all the patients and patients’ guardians.

All patients underwent thyroidectomy combined with either central lymph node (LN) dissection or lateral neck LN dissection. Preoperative and postoperative physical examinations and neck ultrasounds were performed for all participants. Clinical and pathological data of the patients were retrieved from the electronic medical record system of Tianjin Medical University Cancer Institute and Hospital. Pathological diagnoses were independently confirmed by two pathologists in a blinded manner; a third pathologist was consulted to resolve any discrepancies in the diagnostic results. Follow-up information of all 234 CAYA patients was available, and the follow-up period ranged from 48 to 86 months (median follow-up =65 months), time-to-recurrence was from 12 to 63 months (median time-to-recurrence =48 months); 311 older adults’ follow-up period ranged from 52 to 95 months (median follow-up =73 months), time-to-recurrence was from 9 to 63 months (median time-to-recurrence =45 months). The endpoint of follow-up was recurrence or death. Ultrasonography served as the primary imaging modality for follow-up assessments. When imaging studies and fine-needle aspiration cytology identified suspected recurrent lesions (either in the thyroid bed or presenting as lymphadenopathy), surgical resection was subsequently performed to eradicate the lesions and confirm the pathological diagnosis. Biochemical recurrence was not taken into account.

Statistical analysis

The clinical and pathological data of the patients were retrospectively analyzed. SPSS 23.0 and Graphpad 7.0 software packages were used. Categorical data were statistically described as the number (%) of cases. We performed univariate and multivariate Cox regression models to assess independent risk factors. We plotted the log-log survival plots after adjusting for covariates. If the proportional hazards assumption holds, the log-log curves of different groups should remain parallel. In this study, the log-log curves corresponding to all covariates included in the model did not show any significant intersections. Recurrence-free survival (RFS) were curved by log-rank test, Kaplan-Meier, and χ² test were used to evaluate the relationship between lymphatic metastasis and age. P<0.05 was considered statistically significant.

Results

Validation of a unified CAYA cohort: comparability between patients aged <18 and 18–25 years

To evaluate the feasibility of pooling patients aged <18 years with those aged 18–25 years into a single cohort of CAYAs for subsequent analyses, we compared their clinicopathological characteristics using the log-rank test. As summarized in Table 1, the two age groups demonstrated highly comparable clinicopathological profiles, with no statistically significant differences observed across most key features. Only sex distribution differed significantly between the groups (log-rank χ²=4.763, P=0.02), reflecting a higher proportion of male patients in the 18–25 years group. For all other clinicopathological characteristics, including bilateralism (P=0.08), multifocality (P=0.41), papillary thyroid microcarcinoma (PTMC) (P=0.64), Pathological subtype (P=0.40, with Yates’s correction), extrathyroidal extension (P>0.99, with Yates’s correction), nodular goiter (P=0.46), lymphatic metastasis (P=0.17), and postoperative recurrence (P=0.12, with Yates’s correction), no meaningful between-group differences were detected.

Collectively, these results confirm that patients aged <18 years and those aged 18–25 years share highly similar clinicopathological features, with the only distinction being in sex distribution, which is consistent with the previous research results (15). This overall similarity supports treating the two age groups as a single CAYA cohort for integrated analyses (Table 1).

Distinct clinicopathological profiles between CAYA (≤25 years) and older adult (>25 years) patients

Having validated the unified CAYA cohort, we next compared its clinicopathological characteristics with those of older adult patients (>25 years) using the log-rank test (Table 2). Statistically significant differences were observed across multiple key pathological features, indicating a distinct clinical profile in the CAYA population. CAYA patients exhibited higher rates of bilateralism (P<0.01), multifocality (P<0.01), PTMC (P<0.01), extrathyroidal extension (P<0.01), lymphatic metastasis (P<0.01), and postoperative recurrence (P=0.03) compared with older adults. In contrast, no significant between-group differences were detected in sex distribution, tumor subtype, or nodular goiter status, further highlighting the unique pathological landscape of thyroid cancer in the CAYA population.

Multivariable regression analysis identifies independent predictors of postoperative recurrence

To identify independent predictors of postoperative recurrence, we performed a multivariable Cox regression analysis (Table 3). Taking into account the impact of the treatment methods on postoperative recurrence, we also included factors such as the extent of thyroidectomy, the scope of LN dissection, and whether iodine treatment was received in the analysis. Most clinicopathological factors, including gender, bilateralism, multifocality, PTMC, tumor subtype, extrathyroidal extension, nodular goiter, total thyroidectomy, and iodine therapy, did not reach statistical significance as independent predictors. While this analysis revealed that lymphatic metastasis [Wald =6.893; P=0.009; Exp(B) =6.818; 95% confidence interval (CI): 1.627–28.576] and lateral cervical LN dissection [Wald =7.907; P=0.005; Exp(B) =3.044; 95% CI: 1.401–6.613] were strong independent risk factors for recurrence. Since all surgical procedures were carried out in accordance with the corresponding treatment guidelines, lateral neck dissection was determined based on preoperative imaging evaluations and intraoperative pathological examinations. This means that patients who undergo lateral cervical LN dissection are those who have more LN metastases during preoperative assessment. The extent of LN dissection is largely influenced by LN metastasis. Therefore, we believe that this does not mean that undergoing lateral neck dissection makes postoperative recurrence more likely, which is different from what people usually think, so we attribute both of two factors to LN metastasis.

Based on the results of the single-factor regression analysis and clinical experience, we conducted a Cox multivariate regression analysis for LN metastasis, the size of the primary tumor, and the number of primary tumors. The results show that lymphatic metastasis (Wald =6.203; P=0.01; Exp(B) =6.434; 95% CI: 1.487–27.844) remained a significant independent predictor of postoperative recurrence, while multifocality and PTMC showed no significant prognostic value (Table 4).

Impact of lymphatic metastasis on recurrence-free survival

After we concluded that LN metastasis is an independent factor for predicting postoperative recurrence, we conducted a detailed analysis of the number and location of LN metastases. These analyses demonstrated that patients with lymphatic metastasis had significantly worse RFS than those without metastasis (P=0.002). Additionally, we selected the critical value for the number of LN metastases using the receiver operating characteristic (ROC) curve. Patients with ≥4 LN metastases exhibited significantly poorer RFS compared with those with fewer than 4 metastases (P<0.001), and lateral LN metastasis was associated with significantly worse RFS than central LN metastasis (P=0.006) (Figure 1). Collectively, these findings underscore the critical role of lymphatic metastasis—including its presence, quantity, and anatomical location—in predicting postoperative recurrence in CAYA thyroid cancer patients.

Figure 1 Lymph node metastasis was significantly associated with postoperative recurrence. (A) Recurrence-free survival curve of patients with or without lymph node metastasis. (B) Recurrence-free survival curve of patients with different number of lymph node metastases. (C) Recurrence-free survival curve of patients with central or lateral lymph node metastases. **, P<0.01; ***, P<0.001.

Discussion

The distinct biological behaviors between CAYAs and older adults with thyroid cancer are presumably driven by divergent molecular genetic landscapes between the two populations. It is well established that BRAF V600E/RAS mutations and RET-PTC fusions (e.g., RET/CCDC6, RET/NCOA4) are the core oncogenic drivers in thyroid cancer, accounting for approximately 70–80% of genetic aberrations in PTC, the most prevalent subtype (16,17). Notably, accumulating evidence indicates that CAYAs with PTC exhibit a significantly higher frequency of gene fusions (including RET-PTC, NTRK, and ALK fusions) compared to older adults, whereas older adults predominantly harbor BRAF V600E mutations. This molecular discrepancy contributes to the more aggressive phenotypic features of thyroid cancer in CAYAs, characterized by a 60–80% LN metastasis rate and a 10% lung metastasis rate—markedly higher than those in older adults (18). Nevertheless, CAYAs generally achieve longer overall survival than older adults, attributed to their younger age, better tolerance to aggressive treatment, and inherently favorable prognosis following standardized management.

This paradox raises a critical clinical dilemma: should all CAYAs undergo aggressive treatment? Proponents of radical intervention, as supported by international guidelines, argue that residual thyroid tissue is a pivotal risk factor for postoperative recurrence, thereby advocating for total thyroidectomy as the standard approach (10,19). However, total thyroidectomy carries substantial risks of long-term complications, including permanent hypothyroidism requiring lifelong levothyroxine replacement and iatrogenic parathyroid dysfunction—both of which can impair the growth, development, and quality of life in pediatric and adolescent patients (20,21). Furthermore, while total thyroidectomy facilitates adjuvant iodine-131 therapy, cumulative exposure to radioactive iodine elevates the risk of secondary malignancies (e.g., leukemia, salivary gland cancer) in CAYAs, who have a longer life expectancy (21). Thus, accurate preoperative and postoperative recurrence risk stratification is indispensable for tailoring individualized treatment regimens, avoiding overtreatment that compromises long-term outcomes while ensuring adequate disease control.

Epidemiological data consistently demonstrate that sex disparity in CAYA thyroid cancer is not evident before 10 years of age and becomes progressively prominent after 15 years of age, coinciding with pubertal hormonal changes (22,23). Consistent with this trend, our findings reveal a female-to-male ratio of 2:1 in CAYAs, which is substantially lower than that in older adults, and no significant sex-based difference in recurrence risk was observed. This blunted sex disparity in CAYAs is likely multifactorial: gonadal hormone levels (especially estrogen)—a well-documented driver of thyroid cancer gender bias—are relatively stable before puberty and gradually increase during adolescence, resulting in less pronounced hormonal effects compared to older adults (24). Additionally, the smaller thyroid volume and active growth phase in CAYAs may enhance the detectability of thyroid nodules or hormone disturbances, potentially masking subtle sex-related differences in tumorigenesis.

Consistent with previous reports (25), our results confirm that extrathyroidal extension and LN metastasis are more prevalent in CAYAs than in older adults, a feature closely linked to the high gene fusion rate in this population. Notably, most primary tumors in CAYAs are PTMC, which may be attributed to the increased utilization of high-resolution ultrasound in routine screening and the heightened sensitivity of the immature thyroid gland to oncogenic stimuli (26,27). We also observed a higher incidence of multifocal tumors in CAYAs, yet no significant correlation was found between multifocality and postoperative recurrence. This finding underscores the unclear prognostic value of primary tumor characteristics (size, multifocality) in CAYAs, highlighting the need for further large-cohort studies to clarify their clinical significance and guide surgical decision-making—particularly the preference for partial thyroidectomy in CAYAs to mitigate the adverse effects of total thyroidectomy on growth and development (28,29).

Univariate analysis of clinicopathological features in CAYAs identified LN metastasis as a key determinant of postoperative recurrence, which aligns with prior studies confirming the detrimental impact of LN involvement on RFS (30). Additionally, lateral cervical LN dissection was associated with increased recurrence risk, which may reflect preoperative ultrasound-based selection bias: patients undergoing lateral neck dissection often present with more extensive LN involvement, inherently conferring a higher recurrence potential (19,29). While the prognostic relevance of LN metastasis in thyroid cancer has been widely reported, most prior investigations have focused on the presence or absence of metastasis rather than its quantitative and spatial heterogeneity, especially in the CAYA population. To address this knowledge gap, we performed Kaplan-Meier survival analysis to systematically evaluate the effects of LN metastasis burden and anatomical location on RFS—representing a key novelty of the present study. The results demonstrated that CAYAs with a higher number of metastatic LNs had significantly shorter RFS, and lateral cervical LN metastasis was associated with a substantially elevated recurrence risk compared to central compartment metastasis—consistent with the notion that lateral nodal involvement indicates more advanced disease spread (28,30). Cox multivariate regression analysis further validated the number of metastatic LNs as an independent prognostic factor for recurrence, a finding that refines risk stratification beyond the binary classification of metastatic status. Collectively, these findings not only corroborate the established role of LN metastasis in CAYA thyroid cancer recurrence but also provide novel, clinically actionable insights: preoperative imaging modalities (e.g., high-resolution ultrasound, contrast-enhanced CT) can be optimized to quantify metastatic LN burden and define their anatomical distribution, enabling precise recurrence risk stratification and personalized treatment planning to optimize outcomes in CAYAs.

This study is subject to several inherent limitations that warrant acknowledgment. First, despite the more aggressive biological behavior of thyroid cancer in children relative to adults, pediatric thyroid cancer remains a rare disease entity. As a single-center investigation with a relatively limited sample size, the generalizability of our findings could be constrained. Future multicenter collaborations with expanded cohorts are therefore warranted to validate and strengthen these preliminary conclusions. Second, the institutional medical record system utilized in this research requires further optimization. Given that radioactive iodine therapy necessitates close coordination across multiple functional departments, critical clinical details—including iodine-131 dosage regimens and molecular markers—could not be fully retrieved and analyzed. Additionally, patient adherence to long-term postoperative hormonal replacement therapy represents a pivotal determinant of treatment outcomes; unfortunately, such data were not accessible for analysis. Nonetheless, our core findings are consistent with those documented in prior investigations, thereby conferring robust credibility and substantial clinical reference value to the present work. Moreover, our analysis identified lateral cervical LN metastasis as key predictors of postoperative recurrence. Collectively, these observations underscore the imperative of implementing personalized preoperative recurrence risk stratification for CAYA patients with thyroid cancer. Such a tailored approach is essential to strike a balance between therapeutic adequacy and safety, thereby mitigating the adverse consequences of overtreatment (e.g., surgical complications and long-term hormone dependence) while preventing disease recurrence associated with undertreatment.

Conclusions

This study revealed that the presence of LN metastasis, as well as the location and number of metastases, are independent influencing factors for evaluating the risk of postoperative recurrence of thyroid cancer in children, adolescents, and young adults.

Acknowledgments

None.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-1-871/rc

Data Sharing Statement: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-1-871/dss

Peer Review File: Available at https://tp.amegroups.com/article/view/10.21037/tp-2025-1-871/prf

Funding: This study was supported by the Tianjin Education Commission Research Program Project (No. 2023YXZD05).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tp.amegroups.com/article/view/10.21037/tp-2025-1-871/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 present study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. This study was approved by the Medical Ethics Committee of Tianjin Cancer Hospital (No. bc20240001) and informed consent was taken from all the patients and patients’ guardians.

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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