Pediatric Differentiated Thyroid Carcinoma: Outcome in Response to Initial Treatment

Introduction: Though the differentiated thyroid carcinoma in children is a common pediatric endocrine malignancy, its prognosis is excellent with a proper initial treatment. Objectives: This is to evaluate the initial treatment patern for a good prognosis with longterm outcome in pediatric DTC patients. Methods: This study is a prospective one done in BSMMU during a period of 10 years in 52 post operative pediatric DTC patients after excluding the follow-up missing patients. These patients are yet in a regular follow-up were outcome evaluated with clinical, pathological & imaging studies. Results: All the patients got initial treatment of total thyroidectomy. About half of the group had underwent neck dissection along with total thyroidectomy. Forty six patients had taken 131-I therapy. The survival is 100%. Conclusion: The life expectency for children with DTC is excellent. However, many patients experience adverse effects from thyroid surgery, resulting in life long complications.


Introduction
Differentiated thyroid carcinoma (DTC), which comprises papillary thyroid carcinoma (PTC) and follicular thyroid carcinoma (FTC), is a rare disease during childhood. However, DTC is the most common pediatric endocrine malignancy and its incidence is increasing [1][2][3] . The prognosis in children has been reported to be excellent with 15 years survival rates greater than 95% 3 .
The biological behavior of the two carcinomas differ significantly where papillary thyroid carcinoma is known to frequently metastasizes to regional lymph nodes, where follicular thyroid carcinoma more frequently metastasizes to distant organs such as the lung, bone and brain. Pathogenesis of differentiated thyroid carcinoma is multifactorial with both genetic and environmental factors playing an important role 4 For unknown reasons it was found to be 2-4 times more common in women 5 Previous exposure to ionizing radiation including external irradiation of the neck would increase the incidence of cancer especially the papillary type.
Distant metastasis at the time of diagnosis is the most important prognostic factor for both papillary and follicular thyroid carcinomas 6 Extra thyroidal extension and lymph node metastasis are important prognostic factors for papillary thyroid carcinoma while the grade of invasiveness and carcinoma differentiation are important to evaluate the biological behavior of follicular thyroid cancer 7 .
The initial treatment for children with DTC generally consists of a (near) total thyroidectomy with or without lymph node dissection, although for patients with minimally invasive PTC and lacking other adverse risk factors, a less aggressive treatment has recently been recommended 8,9 In most cases, surgery followed by ablation therapy with radioactive iodine (131-I) to destroy residual tumor foci and to facilitate disease monitoring by follow-up scan and measurent of serum thyroglobulin 10 .

Aims & objectives
The objectives of this study were to evaluate the clinical and pathological characteristics, response to initial treatment patern, and longterm outcome of post operative DTC in prepubertal, pubertal, and post-pubertal patients i.e. pediatric patients.

Methods
This prospective study was conducted at Bangabandhu sheikh Mujib Medical University, Dhaka, during, the period of January 2009 to December, 2018. Patients of DTC, age less than 18 years, admitted in the Department of Otolaryngology & Head-Neck surgery of this university and underwent surgery in this period of 10 years, were included in the study .
The data obtained from the medical file of each patient included the following: possible predisposing factors, e.g, hashimoto thyroiditis, familial DTC (first degree relative with DTC); previous exposure to external irradiation; presenting complaint and clinical findings; FNA cytology results; imaging, e.g, cervical US(ultrasonogram), computed tomography (CT) scan of neck and chest or magnetic resonance imaging (MRI) from diagnosis throughout follow-up from initial treatment (extent of operation. Operative findings, 131-I dose) were recorded. Follow up given monthly for 6 months. Every three months for one year and then yearly.

Results
As shown in the study flow chart ( Fig.1) 69 patients with pediatric DTC were identified and treated in our center, the ages ranging from 07 years to 18 years. Overall survival is yet 100% after a median follow-up of 4.5 years (range 0.3-10 years Total thyroidectomy was performed in all patients. In 32 patients (61.5%) the total thyroidectomy was per formed as a single procedure. In the remaining 20 patients (38.5%), a diagnostic hemithyroidectomy was performed, followed by a completion thyroidectomy.
Lymph node dissection (Neck Dissection) was performed as part of initial therapy in 27 patients (51.91%) of which 19 (36.54%) were found positive for metastasis. These patients were underwent lateral neck dissection including levels II-IV±V on one or both sides of the neck (Table-1) Forty seven patients underwent 131-I ablation therapy after surgery. Five patient did not receive 131-I therapy due to consultant's choice.
As shown in Table-2, post operative transient and permanent hypothyroidism were observed in 15(28.85%) and 2(3.85%) respectively. Both transient and permanent hypothyroidism occurred more often in patients who underwent a lymph node dissection. Unilateral RLN (Recurrent Laryngeal Nerve) injury occurred in 6 patients(11.59%). Bilateral RLN injury occurred only in a 13-years old patient who had treated with a total Thyroidectomy, a central compartment dissection and a bilateral Lymph node dissection. RLN injury occurred more often in patients with tumors staged T3-T4 compared with stage T1-T2(P<.001) and in patients with lymph node involvement (P<.001). The frequency of surgical complications did not differ between intial surgery performed before or during the last decade.

Outcome
At the time of the last evaluation , the survival was 100%. At this time point,41 patients (78.85%) were diseasefree. Outcome is similar in all age groups(P=0.103, data not shown) . In 11 patients there is persistent disease or recurrence. Four patients (7.7%) has persistent disease, are classifiend as such based on a detectable Tg level. Six patients (11.54%) developed recurrence within 3.9 to 8 years after initial treatment . Of the five patients who had not been treated with 131-I after total thyroidectomy, one (1.9%) developed a recurrence of disease in the neck . Outcome did not differ between patients with PTC and FTC or between the three age groups.

Discussion
The recently proposed ATA risk of recurrence stratification system aimed to define the likelyhood of recurrent or persistent disease after initial surgery in pediatric DTC and to identify the patients who would benefit from RAI treatment. In the present study, we demonstrated that the application of riskstratification systems according to postoperative findings as well as the response to initial therapy, may facilitate predicting the disease course and outcome. The ATA riskstratification system categorizes pediatric patients into three risk groups according to regional LN and distant metastasis staging by using the tumor node classification system 11 . However, it does not encompass all of the tumor characteristics necessary for accurate assessment of the prognosis after the diagnosis of DTC. In young children the relatively small thyroid nodule volume and its changes with age make it an un-reliable prognostic criterion 12 The cumulative therapeatic 131-I activity during initial treatment and follow-up in our series was relatively high. Given the good survival rate, it can be questioned whether children could just as well be treatment with lower therapentic activities, as suggested by recent guidelines 7,8 . It is our opinion that the administration of 131-I should be considered very carefully in pediatric patients to prevent possible early and late adverse effects 13,14 . This especially the case in children with lowrisk DTC because no benefit of 131-I ablation therapy has been shown in adults with lowrisk disease 15 . High 131-I activities should be reserved for children with metastatic disease, as advocated earlier by Verburg et al 16 .

Strength and limitations
The major strength of our study is that the entire series was followed up at a single center by the same expert multidisciplinary team from diagnosis to the last visit. Thus all aspects of initial management were quite uniform, including extent of surgery, RAI treatment, the degree of TSH suppression, and the rigorous surveillance protocol. The main limitations of our study are the relatively small series and relatively short follow-up period making it imperative that we continue to exercise caution and avoid generalizations when dealing with each individual case.

Conclusion
The life expectency for children with DTC is excellent. However, many patients experience adverse effects from thyroid surgery, resulting in life long complications.