Clinical Assessment of Pediatric Patients with Differentiated Thyroid Carcinoma: A 30-Year Experience at a Single Institution

Thyroid carcinoma is very rare during childhood and accounts for 1.8% of all thyroid malignancies, according to the surveillance, epidemiology, and end results program [1]. Among thyroid carcinomas, differentiated thyroid carcinoma (DTC) is the most common endocrine carcinoma in pediatric patients, accounting for 90–95% of all pediatric thyroid carcinomas [2, 3]. Papillary thyroid carcinoma (PTC) accounts for >90% of all cases of DTC, and follicular thyroid carcinoma is a rare histological type [4, 5].

Pediatric DTC can be differentiated from adult DTC based on several characteristics. The disease is more extensive, with more common extrathyroidal extension (ETE) and a higher risk of recurrence, in pediatric patients [6‐8]. Several studies have reported that the incidence of distant metastasis is up to 25% and that of lymph node metastasis ranges from 40 to 80% [8‐10]. Despite the more aggressive disease features and higher risk of recurrence, the long-term outcome has been reported to be better in pediatric patients than in adult patients [11, 12].

Treatment of pediatric DTC generally involves surgery and postoperative treatment, such as radioactive iodine (RAI) therapy and thyroid-stimulating hormone suppression. Surgery is the main approach for treating DTC, and the extent of surgery ranges from lobectomy to bilateral total thyroidectomy (BTT). According to the American Thyroid Association (ATA) management guidelines, the treatment of choice for pediatric patients with DTC is thyroidectomy, especially BTT [13]. BTT is preferred because of the increased incidence of bilateral and multifocal disease, as well as an increased risk of recurrence [6, 9, 14]. In addition, RAI therapy is administered and thyroglobulin (Tg) serves as a tumor marker when BTT is performed [14, 15]. However, the disadvantages of BTT could lead to various complications, such as transient/persistent postoperative hypoparathyroidism and recurrent laryngeal nerve injury [16, 17]. Permanent hypoparathyroidism may develop in <2.5% of the patients, and permanent recurrent laryngeal nerve palsy may develop in approximately 1% of the patients, even when the procedure is performed by experienced surgeons [18, 19].

This retrospective study aimed to report our experience at a single tertiary institution and to evaluate the risk factors for recurrence, especially based on the extent of surgery, in pediatric patients with DTC.

The incidence of DTC has significantly increased in the last 2 decades and has also steadily increased in pediatric patients [2, 21‐23]. DTC manifests more aggressive features in pediatric patients than in adults; however, the prognosis is better known in pediatric patients [6‐8, 12, 24]. Similar to that in the other studies, lymph node metastasis was observed in 75.5% and ETE was observed in 36.2% of the patients in our study [6‐10, 25]. According to the ATA management guidelines for children, BTT is recommended in pediatric patients with DTC because of the possibility of recurrence owing to the more extensive disease pathology in this population [13]. Other studies have also reported that BTT can reduce the incidence of recurrence compared with lobectomy [6, 9, 26]. However, BTT can cause various postoperative complications, although such complications are rare. The complications can include permanent hypoparathyroidism or vocal cord palsy, which can be associated with serious long-term problems [18, 19]. Although there is a general consensus that surgery is the primary treatment for pediatric DTC, the extent of surgery remains controversial [24]. The main issue is related to the impact of the extent of surgery on recurrence and the potential associated risk of complications. Those who favor BTT claim that the procedure is related to improved DFS without significant complications when performed by experienced surgical teams [26, 27]. However, lobectomy has been proposed to have comparable surgical outcomes in selected patients and is considerably safer than BTT [28].

In the present study, 7 (11.5%) and 7 (21.2%) patients in the BTT and less than BTT groups, respectively, experienced disease recurrence. There was a distinct pattern of recurrence in both groups. In the BTT group, all patients, except one patient, experienced recurrence in the contralateral central compartment. In comparison, 5 of the 7 patients in the less than BTT group experienced recurrence in the thyroid contralateral to the operated side. This is probably due to an invisible multifocal disease on the contralateral thyroid of the lesion at the time of DTC diagnosis. One patient who underwent lobectomy needed a reoperation within 1 month after surgery because of lateral neck node metastasis. It is possible that the lateral neck node metastasis was missed at the time of DTC diagnosis. Thus, we excluded this patient from our study population.

In this study, 1 (2.0%) and 13 (29.5%) patients in the small tumor and large tumor groups, respectively, experienced disease recurrence after the initial treatment. The recurrence rate was significantly higher in the large tumor group than in the small tumor group (p < 0.001), and it was also statistically significant in the Kaplan–Meier analysis (log-rank p < 0.001). However, there was no statistically significant difference according to a tumor size of 1 cm (log rank p = 0.098). Byeon et al. reported that there was no significant difference in the DFS between the papillary thyroid microcarcinoma group and the PTC >1 cm group [29]. Recently, the LNR has been suggested as a significant prognostic factor in adult patients with PTC [30]. Rubinstein et al. reported that the LNR may be a useful predictor of recurrence in pediatric patients with PTC [31]. ROC curve analysis was performed to determine the optimal cutoff LNR of 0.4. However, there was no statistically significant difference in the DFS between the low LNR and high LNR groups (log-rank p = 0.096).

To determine the risk factors associated with the DFS, we conducted univariate and multivariate Cox regression analyses. Only two risk factors, tumor size >2 cm and positive lymph nodes, were identified as significant risk factors for the DFS (HR, 14.241; 95% CI, 1.847–109.828 [p = 0.011] and HR, 1.056; 95% CI, 1.003–1.111 [p = 0.039], respectively). Conversely, the extent of surgery was not a risk factor for the DFS. The less than BTT group showed a high HR; however, this result was not statistically significant in the univariate analysis (HR, 2.171; 95% CI, 0.787–5.989; p = 0.134). Kaplan–Meier analysis for the DFS showed no significant differences between the BTT and lobectomy groups (log-rank p = 0.215). In contrast to the results reported in other studies, the extent of surgery did not affect recurrence in this study, which may be due to differences in the patients’ ethnicity or the patient groups in this study [4, 20, 27, 32]. Demidchik et al. suggested that lobectomy is only acceptable in limited diseases, such as small solitary intrathyroidal lesions without evidence of neck lymph node involvement [4]. Massimino et al. reported that the prognosis was favorable even after recurrence and was not related to the extent of surgery [33]. Therefore, we suggest that lobectomy may be an alternative to BTT, but only for patients with limited disease, such as those with tumor size <2 cm, no suspicious lymph nodes, intrathyroidal lesion, and no multifocal disease. However, the disadvantage of lobectomy is that serum Tg for evaluation of postoperative disease status and RAI remnant ablation cannot be used.

There are some limitations of this study. First, this study was retrospective in nature. Second, there may have been a selection bias because the data were collected at a single tertiary institution and do not represent the entire patient population. Third, the study population included only 94 pediatric patients with a relatively short follow-up period (148.6 ± 81.6 months, range 60–452 months). Fourth, the 30-year data do not reflect the changes in the indication of surgical extent during this period. Finally, 88 (93.5%) patients were aged >10 years and only 6 (6.4%) patients were aged <10 years; therefore, it is unlikely that the results can be generalized to the entire pediatric population.

However, the strength of this study was the follow-up of every patient and the use of a standardized laboratory and imaging protocol at a single institution. Furthermore, to the best of our knowledge, only a few studies have reported the long-term prognosis of pediatric DTC.

According to the ATA management guidelines for children, BTT remains the treatment of choice for pediatric patients with DTC. Decision making regarding the surgical approach and the extent of surgery should strike a balance between the completeness of tumor removal and the quality of life of the patients. The results of this study show that comparable surgical outcomes may be achieved with lobectomy, and lobectomy may, hence, be considered for patients with limited disease, such as those with tumor size <2 cm, no suspicious lymph nodes, intrathyroidal lesion, and no multifocal disease. Further studies are required to determine whether lobectomy is useful in clinical practice for pediatric patients with DTC.