Primary malignancies of the thyroid gland are less frequent in the first two decades of life and accounts for only 0.5-3% of all malignant neoplasms in children and adolescents. The overall incidence of thyroid carcinoma in this population ranges from 1 to 3 cases/million children/year [1]. Similar to adults, there is a female predominance with a female-male ratio of 2.5-6:1 [2]. Thyroid nodules are the most common mode of presentation, but metastatic cervical lymphadenopathy is not uncommon [3]. The incidence of lymph node metastasis (40-80%) and distant metastasis (25%) is higher in the paediatric population [4]. Risk factors identified in the literature include iodine deficiency, previous history of exposure to radiation, underlying thyroid disease, and multiple genetic syndromes [5]. We analysed the trend in children presenting with thyroid carcinoma at our centre, their clinical presentation, biological behaviour, and outcomes.
A retrospective analysis was performed on children less than 18 years of age who were diagnosed with thyroid malignancy at the MVR Cancer Centre and Research Institute over a period of 4 years from June 1, 2018 to May 31, 2022. Electronic health records were reviewed to determine patient demographics, risk factors, family history of any malignancy, pathological characteristics, interventions (surgery and radioactive iodine therapy [RAI]), and follow-up. Patients who were initially treated at a non-oncological centre and referred to our institute for further management were also included in the study.
All the children underwent surgery as the primary treatment modality. Following surgery, a diagnostic radioiodine (I-131) scan was performed after withholding oral thyroxin (for induction of postoperative hypothyroidism) in intermediate- and high-risk patients according to the 2015 Paediatric American Thyroid Associ-ation (ATA) guidelines [5]. Fig. 1 shows the initial post operative staging for intermediate and high-risk paediatric thyroid carcinoma using stimulated Thyroglobulin (Tg) as per ATA guidelines [5]. Stimulated Thyroglobulin (Tg) was done when thyroid stimulating hormone (TSH) levels are high. For adequate stimulation, TSH should be at least 30 m IU/L [6].
RAI therapy was administered for the treatment of iodine-avid persistent locoregional or nodal disease that was deemed unresectable and for known or presumed iodine-avid distant metastases. In patients with persistent disease, 131 therapies were decided according to the clinical status and previous response to treatment. The I-131 dose was calculated based on the 2015 ATA guidelines for paediatric thyroid cancer. Tumour staging was performed based on the tumor-node-metastasis (TNM) classification system according to the latest American Joint Committee on Cancer [7]. All patients were classified as stage 1 (any T, any N, M0) or stage 2 (any T, any N, M1) after obtaining a histopathological report of the thyroidectomy specimen.
At follow-up, clinical examination, biochemical assessment, and radiological evaluation were performed every 6-8 months. The absence of structural, functional and biochemical evidence of disease was defined as complete remission (CR). Biochemical, functional or structural increase of disease detected by imaging and blood tests was considered to be progressive disease (PD). No significant change in structural, functional or biochemical parameters of disease was considered to be stable disease. Imaging modalities such as Ultrasound (USG) with or without Computed Tomography (CT scan) were used for assessing structural disease. Diagnostic 131I scan was used to assess functional disease. Biochemical disease was assessed by serum thyroglobulin and antithyroglobulin antibody. The presence of histologically or radiologically proven disease in the thyroid bed was defined as local recurrence, recurrence of disease at the sites of lymphatic drainage was defined as nodal recurrence, and the presence of disease either radiologically or histologically in any distant organ or lymph node was defined as distant metastasis.
Data were analysed using IBM SPSS statistical software version 20.
Over the study period of 4 years, 1,502 newly diagnosed patients with thyroid carcinoma were treated in our centre. Among the analysed cohort, 18 (1.2%) patients were younger than 18 years at the time of diag-nosis. Table 1 shows the demographic variables collected in this study. The mean age at diagnosis was 14.7 years (range, 6-18 years). Majority were females and, in the post, pubertal age group. No risk factors were identified in any of our children but one child had a concomitant Burkitt lymphoma.
Table 1 . Demographic variables.
Gender | |
Male | 5 (28%) |
Female | 13 (72%) |
Age | |
Mean | 14.7 years |
Range | 6-18 years |
Pubertal status | |
Prepubertal | 5 (38%) |
Postpubertal | 13 (62%) |
Clinical presentation | |
Lymphadenopathy | 7 (39%) |
Thyroid swelling | 18 (100%) |
Radiological evaluation | |
Ultrasonography (USG) neck | 18 (100%) |
Computed tomography (CT) chest | 3 (16.6%) |
USG guided fine needle aspiration cytology (FNAC) | 18 (100%) |
Surgery | |
Total thyroidectomy | 17 (94.4%) |
Hemithyroidectomy | 1 (5.6%) |
Neck dissection | |
Central neck dissection | 7 (38.9%) |
Central and unilateral neck dissection | 3 (16.7%) |
Central and bilateral neck dissection | 5 (27.7%) |
None | 3 (16.7%) |
Histology | |
Papillary – classic | 14 (77.9%) |
Follicular | 3 (16.6%) |
Diffuse sclerosing | 1 (5.5%) |
Extension | |
Thyroid only | 8 (44.4%) |
Cervical node involvement | 10 (55.5%) |
Lung | 3 (16.6%) |
Radioiodine therapy | |
Yes | 15 (83.3%) |
No | 3 (16.7%) |
Seventeen patients underwent total thyroidectomy and one patient underwent hemithyroidectomy. All our children had papillary thyroid carcinoma; follicular variant was noted in 16.6%, and diffuse sclerosing in 5.5%. Fig. 2 shows the pathological characteristics of the patients. Regarding pathological characteristics, extensive lymph node (LN) involvement, defined as involvement of more than 2 LN, was noted in 44.4% of patients. Extra nodal involvement, lymphovascular invasion, and extra thyroidal involvement were seen in 16.6%, 61.1%, 16.60% of patients, respectively.
According to the TNM classification, 8 patients were classified as T1-4N0M0, 2 patients were classified as T1-4N1aM0, 5 patients were classified as T1-4N1bM0, and 3 patients were classified as T1-4N0-1M1. 83.4% had stage I disease, whereas 16.6% had stage II disease. Lung involvement was noted in 16.6%. Risk stratification revealed that 44.6% of the children were in the high-risk group and 38.8% were in the intermediate-risk group.
Among the eighteen children, fifteen patients (83.3%) required I-131 therapy. More than three cycles of I-131 therapy were required in 13.3% of patients. 73.4% had one cycle of I-131 therapy and 13.3% had three cycles of I-131 therapies. 26.7% received cumulative dose of 50 mCi, 40% had received dose of 100 mCi, 6.7% received dose of 150 mCi, and 26.60% received >150 mCi dose of I-131. Fig. 3 shows the I-131 cumulative dose and number of I-131 cycles.
Follow up period ranged from 2-51.7 months with a median follow up period of 22.15 months. Complete remission was noted in 15 patients (83.3%). Out of the children with metastatic lung disease, 1 had progressive disease, 2 had stable disease. Overall survival was 100% and progression free survival was 36 months.
Differentiated thyroid carcinoma (DTC) though rare in children when compared to the adult population, it remains to be the most common endocrine malignancy in children less than 18 years of age. The clinical pattern of thyroid carcinoma in children and adolescents varies from that in adults in terms of a more advanced stage of presentation but better response to treatment, resulting in an excellent prognosis.
SEER data base in the period 1980-2016 showed an increase in incidence rate of DTC in the United States from 2.39 to 7.54 per 100,000 in men and from 6.15 to 21.28 per 100,000 in women [8]. Most published data from the Western population suggest an increase in DTC in childhood [9,10]. Unfortunately, in the last two decades, comprehensive, high-quality evidence of DTC has not been published in India. A global database covering 49 countries and five continents has shown a rapid increase in incidence in almost all countries during the time period–2008-2012 as compared to the data before 2000 [9]. Published data from the United States suggest an increasing trend for both male and female children [10]. A population-based study from Cyprus, the country with the highest incidence of thyroid cancer, has shown the incidence to be rising mainly in children between 15-19 years of age and increasing incidence of metastatic disease [11]. There have also been conflicting data from other countries, such as Denmark, in which a nationwide study did not show an increase among children but showed a rise in young adults between 18-24 year of age, mainly attributed to an increase in papillary carcinoma in females [12].
A global survey by Vaccarella et al. suggested a role of overdiagnosis leading to unnecessary overtreatment affecting the quality of life over a lifetime [9]. These claims have been refuted by the majority of authors. Vergamini et al. from the United States rules out diagnostic scrutiny as the sole reason for the rise but suggests that environmental, genetic and dietary factors should be investigated [10]. The authors from Cyprus suggest that there is a definite increase in metastatic disease that cannot be explained by overdiagnosis alone [11]. Most data from Indian subcontinent are a decade old and we don’t have data to suggest a rising incidence [13-15].
The contribution of Paediatric DTC has varied from 1.8-5% among all thyroid malignancies in various studies conducted worldwide [16]. In our analysis of the 1,500 patients, 18 were children aged <18 years (1.2%). Most thyroid cancers occur in children aged >10 years and in post-pubertal children. The incidence in children under 10 years of age is approximately 1 per million [17]. A tenfold increase occurs as the child enters adolescence. Younger children have more aggressive tumours and higher mortality rates. In a study by Kumar et al., 2.5% of the mortality in their cohort occurred in children aged <10 years [18]. In our study, children less than 10 years constituted 11% and 50% of them had advanced disease with lung metastasis. Similar to the adult population, there is a three times greater preponderance in girls than in boys, but this is almost equal in prepubertal children [14]. Even in our study, in children aged >10 years, females were three times more likely to be affected than males, but in children aged <10 years, the male:female ratio was 1:1. It has been suggested that hormonal changes during puberty in girls might predispose to the development of DTC. Due to these differences, the ATA committee proposes that prepubertal and post pubertal statuses should be incorporated in future studies on paediatric DTC [5].
Low-dose radiation has been proposed as an important risk factor for DTC development in children [5]. Richardson et al. have demonstrated high occurrence rate of thyroid carcinoma in atomic bomb survivors [19]. High-risk populations with a high incidence are childhood cancer survivors who are treated for their primary malignancy with radiation therapy, especially survivors of Hodgkin lymphoma, leukaemia, and central nervous system tumours [20]. None of the studies from India showed a relationship with radiation exposure [18]. None of our children had any history of radiation exposure but one of our children had a concomitant Burkitt’s lym-phoma. Approximately 5% of children have a family history of DTC; these tumors behave aggressively and have a poor prognosis [5]. There were no children with features suggestive of MEN syndrome or autoimmune thy-roiditis.
Although the most common presentation of papillary carcinoma thyroid (PTC) is a thyroid nodule, lymph node involvement as the sole presenting symptom is common in children. A study conducted by Haveman et al. reported that the incidence of cervical lymphadenopathy at initial presentation varies from 35% to 83% [21]. Clinically palpable cervical nodes were present in 39% of children. Distant metastasis, mainly limited to the lungs, is also more common in the paediatric population. Various studies have reported pulmonary metastases in the range of−20-30% [22]. In our study, the majority of patients (83.4%) presented with extensive nodal involvement and lung metastasis, and lung involvement was present in three of our patients (16.6%). This high incidence of advanced disease is mainly attributed to the unique tumour biology and pathological behaviour in children, especially in the age group of less than 10 years, in whom the majority of PTCs are unencapsulated, diffusely involve the thyroid gland, have extrathyroidal invasion, and with specific pathological subtypes such as follicular and solid being more common. Most DTC cases in children are PTC, with rare variants being more common. Nevia et al. reported PTC in 86.9% cases with diffuse sclerosing and follicular variant in 8.7% and 30.4% of children respectively [23]. All our children had PTC; follicular variant was noted in 16.6%, and diffuse sclerosing in 5.5%.
In comparison to adult PTC, the prevalence of gene rearrangement is higher and point mutations are lower in children. BRAF and RAF point mutations mainly observed in adults, lead to genomic instability, which is responsible for the dedifferentiation of DTC to the anaplastic type. RET/PTC rearrangements observed in children do not lead to genomic instability, which is responsible for the good response to RAI treatment and better survival [5]. Despite having an advanced stage of presentation, children usually have better survival rates than adults. Even in the presence of metastatic disease, the majority have a survival of 90-99% and lung lesions can remain stable over prolonged periods of time. Nation-wide data from Cyprus have reported 100% survival rates in patients with metastatic disease [11]. Samuel et al. in his data on children with well differentiated thyroid cancer has demonstrated low mortality in spite of achieving only a partial response after RAI therapy [13]. In our cohort of children, all subjects with or without metastatic disease survived, with a median follow-up of 22 months (range, 2-51 months). Among our three children with lung metastasis, persistent lung metastasis was observed in 66% of the children after multiple RAI therapies, and they remained asymptomatic. One of the children had progressive lung lesions but remains to be on follow-up.
Dose of 131I to treat residual disease in children is based on body weight (1.0-1.5 mCi/kg; 37-56 MBq/kg). In general, a 5 year old child may require one third of the adult activity for similar extent of disease. A 10 year old child may require one half of the adult activity, 15 year old may require five sixths of adult activity. Ideal frequency of 131I has not been determined. Maximum clinical and biochemical response from 131I may not be reached for up to 15-18 months. Effects of therapy can be seen well beyond the first years after treatment. It may take years to see the full response of 131I [5]. Chesover et al. did not find any association between number of RAI cycles and structural outcome. They reported that treating non-responsive disease with cumulatively higher RAI doses might not improve outcome [24].
With the discovery of aberrant RTK and MAPK/PI3K pathways in thyroid malignancies, tyrosine-kinase inhibitors (TKI) has emerged as one of the final therapeutic options for resistant and aggressive tumours which are incurable with surgery or RAI. The drugs that are approved for use in DTC are Sorafenib and Lenvatinib. Vandetanib and Cabozantinib have been found to be useful in metastatic and progressive medullary carcinoma thyroid. More specific TKIs, like BRAF inhibitors such as Dabrafenib, NTRK inhibitors like Larotrectinib and Entrectinib, and RET/MET inhibitors, are also being used in thyroid malignancies [25]. Studies of the effectiveness and long term toxicity of these newer agents in the paediatric population is limited.
The main limitation of our study is that it was conducted over a short period of 4 years, and the follow-up duration was not long enough. Considering that thyroid malignancies are very rare in children, only a nationwide multicenter analysis can provide data on the actual prevalence and prognosis.
Majority of our children with DTC presented with nodal and distant metastasis, although all of them had good survival. Even among children with pulmonary metastasis, all children survived during the follow-up period despite having progressive disease. There was no incidence of undifferentiated carcinoma in our cohort of children.
Children with DTCs should be kept under strict follow-up to detect local or distant metastases. Further studies are needed to better understand the patterns of paediatric thyroid carcinomas.
The authors have no conflict of interest to declare.