Clinical Implications of Age in Differentiated Thyroid Cancer: Comparison of Clinical Outcomes between Children and Young Adults

Background Pediatric patients with differentiated thyroid cancer (DTC) present with unique characteristics compared to adult patients. This study aimed to evaluate clinical presentation and surgical outcomes according to age and to identify the clinical significance of age in DTC. Methods In total, 98 pediatric patients, 1261 young adult patients, and 4017 adult patients with DTC who underwent thyroid surgery between January 1982 and December 2012 at Yonsei University Hospital (Seoul, Republic of Korea) were retrospectively reviewed. The mean follow-up duration was 120.4 ± 54.2 months. Results Mean tumor size was significantly larger in the pediatric group than in the adult groups (p < 0.001). The recurrence rate was significantly higher in the pediatric group (14.3% versus 6.6% versus 3.0%, p=0.004 and p < 0.001). In multivariate analysis, the risk of disease-free survival (DFS) was lower in the adult group (HR, 0.362; p < 0.001). Reanalysis of patients with tumor size of 2–4 cm revealed that the adult group was not a significant risk factor for DFS in multivariate analysis (HR, 0.305; 95% CI, 0.158 to 0.588; p < 0.001). Conclusions Our findings suggest that pediatric patients present with more aggressive features and higher recurrence rates compared to adult patients and should be carefully treated from initial evaluation to surgery and postoperative care.


Introduction
yroid cancer is the most common endocrine malignancy, and its global incidence has increased over the past two decades [1][2][3][4]. e general use of high-resolution ultrasonography has increased the identification of small nodules, which may be undetected by physical examination. yroid cancer during childhood is rare and accounts for 1.5% to 3.0% of all childhood cancers, but reports indicate that this incidence is increasing [2,5,6]. Papillary thyroid cancer (PTC) is the most common thyroid cancer in both pediatric and adult patients. Follicular thyroid cancer (FTC) is the second most common thyroid cancer but is rare during childhood [7,8].
Pediatric patients with differentiated thyroid cancer (DTC) present with several unique characteristics compared to adult patients. Compared to adult DTC, pediatric DTC tends to manifest as a more advanced disease at the time of diagnosis and is characterized by a more common extrathyroidal extension (ETE), lymph node metastasis, distant metastasis, and a higher risk of recurrence. Nevertheless, long-term prognosis has been reported to be better in pediatric patients than in adult patients [9][10][11].
Treatment of both pediatric and adult DTC comprises surgery, radioactive iodine (RAI) therapy, and thyroidstimulating hormone (TSH) suppression therapy. According to the American yroid Association (ATA) management guidelines for children with DTC, the surgery of choice in pediatric DTC is total thyroidectomy (TT), which is preferred due to the more aggressive features of pediatric DTC, such as ETE and bilateral or multifocal disease [12]. e incidence of pediatric DTC increases with age and is more predominant in females. Most of the patients are diagnosed in adolescence, and adolescents between 15 and 19 years of age have a 10-fold higher incidence compared to the younger population [3,13,14]. Nevertheless, the differences in clinical presentation and clinical outcomes between pediatric and adult patients with DTC remain unclear.
is retrospective study therefore aimed to evaluate the clinical presentation and surgical outcomes of patients with DTC according to age and to identify the clinical significance of age in patients with DTC. Our findings indicated that pediatric patients with DTC tended to exhibit a more aggressive clinical presentation. Further, we identified age as an independent risk factor for disease-free survival (DFS), underscoring the need to ensure careful and appropriate treatment of pediatric patients with DTC.

Patients.
In total, 110 pediatric (<20 years old) patients, 1338 young adult patients (20-29 years old), and 4243 adult patients (30-39 years old) with DTC who underwent thyroid surgery at Yonsei University Hospital (Seoul, Republic of Korea) from January 1982 to December 2012 were retrospectively reviewed. In total, 12 pediatric patients, 77 young adults, and 226 adults were excluded owing to loss at followup and/or inadequate follow-up data. Baseline clinicopathological characteristics of study patients are presented in Table S1. All patients were analyzed by a complete review of medical charts and pathology reports. Of patients, 2620 (48.7%) underwent lobectomy and/or contralateral partial thyroidectomy (less than TT) with prophylactic or therapeutic ipsilateral central compartment neck dissection (CCND) and 2756 (51.3%) underwent TT with prophylactic or therapeutic ipsilateral CCND. Of patients who underwent TT, 691 (12.9%) underwent TT with therapeutic modified radical neck dissection (mRND) due to clinically suspicious or pathologically confirmed N1b nodes. e mean follow-up duration was 120.4 ± 54.2 months (range, 71-391). e study was conducted in accordance with the Declaration of Helsinki (as revised in 2013) and was approved by Yonsei University's institutional review board (IRB No.: 4-2019-0146), which waived the requirement for informed consent due to the retrospective nature of this study.

Postoperative Management and Follow-Up.
All pediatric and adult patients were postoperatively managed according to the ATA management guidelines for children [12] and adults [15], respectively. RAI ablation was performed 4 to 6 weeks postoperatively using doses based on ATA guidelines. Whole-body scans (WBS) were performed after 5 to 7 days of RAI ablation in patients who underwent TT.
yroglobulin (Tg) and antithyroglobulin antibody (TgAb) concentrations were assessed after TSH stimulation by T4 withdrawal or recombinant human TSH injection before RAI ablation. All patients received L-thyroxine with suppressive doses and were regularly followed up with physical examination, thyroid function tests, assessment of Tg and TgAb concentrations, and neck ultrasonography every 3 to 6 months and annually thereafter. Patients who presented with evidence of recurrence or distant metastasis on routine follow-up evaluations were assessed by additional diagnostic imaging, including computed tomography, positron emission tomography-computed tomography, and/or RAI WBS, to determine the location and extent of suspected recurrence. Disease recurrence was confirmed by imaging modalities and/or pathologic diagnosis using ultrasonography-guided fine-needle aspiration.

Statistical Analysis.
Continuous and quantitative variables are presented as means and standard deviation (SD). Categorical and qualitative variables are reported as numbers with percentages. Student's t-test, chi-square test, or Wilcoxon rank-sum test was used for group comparisons. Univariate and multivariate Cox regression analyses were performed to identify independent predictors of DFS. Hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated. DFS was analyzed for the three study groups using Kaplan-Meier survival analysis with a log-rank test. P < 0.05 was considered statistically significant. All statistical analyses were performed with the software package SPSS (version 23.0 for Windows; SPSS, Chicago, IL).

Comparison among Different Age Groups.
A total of 98 pediatric, 1261 young adult, and 4017 adult patients were enrolled in this study. Table 1 presents the results of the comparison of baseline clinicopathological characteristics among the different age groups. e mean tumor size was significantly larger in the pediatric group than in the adult groups (2.1 ± 1.3 versus 1.3 ± 1.0 versus 1.0 ± 0.8, p < 0.001 and p < 0.001). e proportion of FTC was significantly higher in pediatric patients (7.1% versus 1.6% versus 0.7%, p � 0.002 and p < 0.001). With regard to pathological T and N stages, the pediatric group exhibited a significantly higher grade. e recurrence rate was significantly higher in the pediatric group (14.3% versus 6.6% versus 3.0%, p � 0.004 and p < 0.001). No significant differences were observed in gender, multifocality, bilaterality, or ETE among groups. Table 2 presents the results of the comparison of management among the different age groups. e proportion of TT and mRND was significantly higher in the pediatric group than in the young adult and the adult groups (TT, p < 0.001 and p < 0.001; mRND; p < 0.001 and p < 0.001, respectively).

Risk Analysis for DFS in Different Age Groups.
Univariate and multivariate Cox regression analyses were performed to identify independent risk factors for DFS (Table 3). In univariate analysis, the pediatric group was identified as a significant risk factor for DFS ( Figure 1). Tables 4 and 5 present the results of subanalyses of clinicopathological characteristics and management in pediatric subgroups (≤16 years old or 17-19 years old). No significant differences were observed in tumor size, type of carcinoma, multifocality, bilaterality, or M stage between the two pediatric subgroups. e proportion of female patients was significantly higher in the older pediatric group than in the younger pediatric

Subanalysis of Older Pediatric Subgroup and Adult
Groups. Tables 6 and 7 present the results of the subanalyses of clinicopathological characteristics and management of the three different groups over 16 years of age. No significant differences in most of clinicopathological characteristics were identified relative to the results presented in Table 1.  However, the recurrence rate did not differ between the older pediatric and the young adult groups (13.1% versus 6.6%, p � 0.064). e extent of operation and RAI therapy were not significantly different. Univariate and multivariate logistic regression analyses were performed to determine independent risk factors for DFS (Table 8). Results were similar to those presented in Table 3. Only the adult group was not identified as a significant independent risk factor for DFS in multivariate analysis (HR, 0.362; 95% CI, 0.206 to 0.627; p � 0.006). In Kaplan-Meier analysis, no significant difference was observed in DFS between the younger pediatric and older pediatric groups (p � 0.560; Figure 2). Significant differences in DFS were observed between the older pediatric group and adult groups (older pediatric versus young adult group, p � 0.042; older pediatric versus adult group, p < 0.001; Figure 2).

Subanalysis of Patients in Different Age Groups with
Tumor Size of 2 to 4 cm. Given that the majority of pediatric patients were diagnosed with palpable masses rather than by a screening test, we reanalyzed the patients with tumor sizes of 2 to 4 cm. In total, 47 pediatric, 187 young adult, and 367  International Journal of Endocrinology 5 adult patients were included in the reanalysis. Table 9 presents the results of the comparison of clinicopathological characteristics among the three different age groups with tumor sizes of 2 to 4 cm. No significant differences were observed in the proportion of males, type of carcinoma, multifocality, bilaterality, ETE, and pathological T or M stage. e pediatric group presented with a significantly higher grade in the pathological N stage (p � 0.006). Recurrence rate was significantly higher in the pediatric group (25.5% versus 16.6% versus 9.5%, p � 0.001).

Risk Subanalysis for DFS in Patients in Different Age
Groups with Tumor Size of 2 to 4 cm. Univariate and multivariate logistic regression analyses were performed to determine independent risk factors for DFS in patients with tumor sizes of 2 to 4 cm (Table 10). Among the three different age groups, only the adult group was not a significant risk factor for DFS in both univariate and multivariate analyses (HR, 0.292; 95% CI, 0.151-0.563; p < 0.001; and HR, 0.305; 95% CI, 0.158-0.588; p < 0.001, respectively). Bilaterality (HR, 1.758; 95% CI, 1.061-2.913; p � 0.029) was confirmed as a significant risk factor for DFS in multivariate analysis. Kaplan-Meier analysis revealed significant differences in DFS between the pediatric group and adult groups (pediatric versus young adult group, p � 0.045; and pediatric versus adult group, p < 0.001; Figure 3).

Discussion
Pediatric and adult DTCs are considered distinct diseases, as the former is underscored by more aggressive features but a more favorable long-term prognosis [9,11,16]. Age is a major prognostic factor in DTC [17]. erefore, the TNM staging system of DTC is classified according to an age of 55 years. Nevertheless, few studies have compared clinical presentation and surgical outcomes between pediatric and adult patients with DTC [18,19]. Here, we investigated the clinicopathological characteristics of 5376 patients with DTC to investigate the effects of age on surgical outcomes.
In this study, tumor size was larger in pediatric patients. Kim et al. reported that tumor size was larger in pediatric patients than in young adult patients [19]. However, no significant differences were observed in multifocal and bilateral disease between pediatric and adult groups, in contrast to previous reports [20][21][22][23]. Several reports have indicated that the incidence of multifocality in pediatric patients may reach 88% [24,25].
e ETE appeared to be more common in pediatric DTC, but we did not identify a significant difference in this regard. e thyroid gland is smaller in children than in adults, which may facilitate the occurrence of early capsular extension [26]. T, N, and M staging grade and the recurrence rate were significantly higher in the pediatric group than in the adult groups. ese results were consistent with previous reports on the characteristics of pediatric DTC [27][28][29][30]. Nevertheless, the factors underpinning the more aggressive features of pediatric DTC have not been fully elucidated.
Based on the mean age of pediatric patients (16.7 years), we performed a subanalysis of the pediatric group. e ETE was more prevalent in the younger pediatric group (≤16 years old) than in the older pediatric group (17-19 years old). Further, the younger pediatric group presented with a significantly higher grade of T and N stage compared with the older pediatric group. ese findings are consistent with previous reports [27,31,32]. Nevertheless, no significant differences were observed in multifocality, bilaterality, and ETE between adolescent and adult groups. Adolescent DTC tended to be similar to that in young adults, even the recurrence rate.
In multivariate analysis, only the adult group was not identified as a significant independent risk factor for DFS, suggesting that pediatric and young adult DTC have similar clinical outcomes. In addition, the frequency of intensive treatment, such as TT, mRND, and high-dose RAI therapy (>100 mCi), was significantly higher in the pediatric group than in the adult groups. ese factors may have contributed to the similar prognosis of pediatric and young adult DTC. In general, most of adult DTCs were diagnosed with a screening test, whereas most of pediatric DTCs were incidentally diagnosed. Physical examination is important given that palpable masses are more common in pediatric patients than in adult patients [10,[33][34][35]. Indeed, 31-97% of pediatric patients with DTC present with a bulge in the anterior neck [4,10,36]. However, this manifestation is asymptomatic in childhood and is often noticed by parents or medical staff, rendering an early diagnosis of pediatric patients challenging. In this study, the mean tumor size of pediatric DTC was significantly larger than that of adult DTC. Further, we performed a subanalysis of clinicopathological characteristics in three different age groups with a tumor size of 2 to 4 cm. Despite adjusting for size differences, the recurrence rate was significantly higher in the pediatric group than in the adult groups (25.5% versus 16.6% versus 9.5%, p � 0.001). Multivariate analysis revealed similar results to the preceding analyses. Our findings suggest that the prognosis of pediatric DTC is affected by other risk factors, such as age and bilaterality, in addition to tumor size. Jarzab et al. reported that younger children had a poorer prognosis compared to older children [32]. Additionally, Palmer et al. demonstrated that one of the best predictors of recurrence was multiple thyroid nodules at presentation [37]. e causative factors of differences in clinicopathological features and long-term outcomes between pediatric and adult DTC are obscure. One possible factor is differences in molecular pathogenesis between pediatric and adult DTC. Genetic studies of DTC indicate that the most common genetic defect is RET/PTC rearrangements in pediatric DTC, whereas BRAF V600E and RAS mutations are most commonly detected in adult DTC [9,[38][39][40]. Additionally, the level of sodium-iodide symporter (NIS) gene expression is higher in pediatric DTC than in adult DTC [41,42].
is implies greater responsiveness to RAI and better therapeutic outcomes in pediatric DTC than in adult DTC [42,43].
According to the ATA management guidelines for children, TT is recommended in pediatric DTC due to the more aggressive features and increased risk of recurrence in pediatric DTC [12]. In addition, TT has several advantages, such as guaranteed RAI ablation and the use of Tg as a tumor marker. Nevertheless, TT is associated with various complications, including transient/permanent postoperative hypoparathyroidism, recurrent laryngeal nerve injury, and side effects due to lifetime TSH suppression. In this study, none of the pediatric patients developed permanent complications. Conservative surgical management is recommended to avoid surgical complications in pediatric patients with the nonadvanced disease. e optimal extent of operation for pediatric DTC remains under debate. e major controversial factors are the impact of extensive operations on recurrence and potential risks. ose who favor TTclaim that this procedure is associated with improved DFS without significant complications if performed by experienced professionals. Handkiewicz et al. concluded that TT was able to remove all malignant tissue, decrease recurrence risk, and improve patient outcomes [31]. In contrast, those who favor conservative treatment claim that the less aggressive approach is associated with comparable surgical outcomes in selected patients and is considerably safer than TT. Gulcelik et al. advocated less aggressive treatment to decrease the risk of surgical complications [44]. Due to the low incidence, slow progression, and need for long-term follow-up to identify precise diagnosis in pediatric patients, the gold standard operative approach for pediatric DTC remains controversial. A strength of this study is that all patients were treated and followed up with the same protocol comprising surgery, TSH suppression, RAI therapy, and use of imaging modalities by a multidisciplinary team. However, several limitations of the study should be addressed. First, the study    International Journal of Endocrinology design was retrospective in nature. Second, there may have been selection bias given that patient data were collected from a single tertiary institution and may not reflect the entire patient population. ird, of the study population, only 98 patients were in the pediatric group, which was significantly smaller than the other groups. Fourth, the mean follow-up period was relatively short (120.4 ± 54.2 months). is follow-up time limited our ability to compare long-term surgical outcomes between the three different age groups. Finally, only six (6.4%) pediatric patients were below 10 years of age, and the mean age of pediatric patients was 16.7 years. As such, this sample may not have been reflective of the entire pediatric population.

Conclusions
To the best of our knowledge, there is a paucity of studies comparing clinical presentation and surgical outcomes between pediatric and adult groups. is study demonstrated that pediatric patients presented with more aggressive features compared to adult patients. Further, the recurrence rate of DTC was higher in pediatric patients than in adult patients. Given that age was identified as an independent risk factor for DFS, our findings underscore the need for pediatric patients with DTC to be carefully treated from initial evaluation to surgery and postoperative care.
Data Availability e data that support the findings of this study are available upon request from the corresponding author. e data are not publicly available due to privacy or ethical restrictions.

Conflicts of Interest
e authors declare that there are no conflicts of interest.