Pediatric thyroid cancer: key considerations based on the 2024 Korean Thyroid Association Differentiated Thyroid Cancer Management Guidelines

Eun Kyung Lee; Young Ah Lee

doi:10.6065/apem.2448296.148

To the editor,

The incidence of pediatric thyroid cancer has increased worldwide, and the age-standardized incidence rate in South Korea was 0.92 per 100,000 person-years during 2004–2016, with an annual percentage of 4.0% [1]. Pediatric patients, comprised mostly of those with papillary thyroid cancer (PTC, 80%–90%), typically present with a palpable neck mass with advanced stage, and the recurrence rate is high. However, cancer-specific mortality is low, showing a good long-term survival prognosis. Oncogenic fusions (RET, NTRK, ALK, etc.) predominated in children younger than 10 years with PTC, whereas point mutations (BRAF, etc.) increased with age, becoming most common in adolescents aged 15–19 years [2]. Pediatric follicular thyroid carcinoma (FTC) has a very low frequency (<10%), with a more favorable prognosis than PTC. DICER1 and PTEN mutations predominate in pediatric FTC [3], and the possibility of hereditary tumor syndrome needs to be excluded.

Considering the differential biologic features of pediatric thyroid cancer compared to adult thyroid cancer, pediatric-specific guidelines are needed. We, the Korean Thyroid Association (KTA) Guideline Committee on the Managements of Thyroid Nodule and Cancer, published the guideline for pediatric differentiated thyroid cancer (DTC) in International Journal of Thyroidology in May 2024 [4]. The 2024 KTA pediatric DTC guideline consists of 7 parts: preoperative evaluation, children at high risk for developing DTC, surgery, initial treatment and follow-up strategy, radioactive iodine (RAI) therapy, recurrent or persistent disease, and RAI-refractory thyroid cancer (Supplementary Table 1).

Below are the essential aspects of the KTA pediatric guideline [4]:

1. Preoperative evaluation

In pediatric patients with confirmed extrathyroidal extension (ETE) or lymph node (LN) metastasis, imaging studies including lateral neck and mediastinal LNs should be performed to determine the extent of surgery.

2. Children at high risk for DTC

Genetic testing is recommended when hereditary tumor syndrome [5,6] is suspected (Table 1) [4]. A careful assessment of past or family history (multinodular goiter, and thyroid or other tumors of embryonal origin), skin findings, and head circumference is required.

For childhood cancer survivors who have undergone total body or neck irradiation, total thyroidectomy is recommended, and treatment decisions should consider related complications.

3. Surgery

Total thyroidectomy by a high-volume thyroid surgeon is the treatment of choice for pediatric patients, while lobectomy may be considered for low-risk papillary microcarcinomas [7]. In patients with advanced stage, prophylactic central neck dissection (ND) may be performed. If central or lateral LN metastasis is confirmed, therapeutic central and lateral ND should be performed.

4. Initial treatment plan and follow-up strategy (Fig. 1)

Postoperatively, it is recommended to establish an initial treatment and follow-up plan based on a 3-tier Pediatric Risk Classification (low-, intermediate-, and high-risk) according to tumor size, ETE, and extent of metastasis [6]. Details of the initial treatment plan and follow-up strategy based on the 3-tier Pediatric Risk Classification are described in Fig. 1 [4]. In intermediate- and high-risk groups, the measurements of thyroid-stimulating hormone (TSH)-stimulated thyroglobulin (Tg) level and diagnostic scan are recommended to determine the need for RAI therapy.

5. RAI therapy

The decision for RAI therapy should be based on a multidisciplinary evaluation of its benefits and risks. RAI therapy is recommended for iodine-avid pulmonary metastasis and inoperable locoregional lesions. The dose of RAI therapy is determined by weight-based empirical dosing or the calculated maximum tolerable radiation dose, depending on therapeutic goals.

6. Recurrent or persistent disease

In pediatric patients with elevated serum Tg or Tg antibodies during follow-up, neck ultrasound should be performed first. Surgery is the primary option for resectable lesions, while RAI therapy can be performed for inoperable recurrent or persistent lesions if RAI uptake is confirmed.

Iodine-avid pulmonary metastasis should be monitored at appropriate intervals to assess treatment response after RAI therapy. Considering that the majority of pulmonary metastasis does not show a complete remission or it may require years to show a complete remission [8], undetectable Tg levels should not be the goal, and longer intervals between RAI therapy are considered in nonprogressive disease. For progressive iodine-avid pulmonary metastasis, additional RAI therapy is considered, balancing risks and benefits.

7. RAI-refractory thyroid cancer

Pediatric patients with asymptomatic, nonprogressive RAI-refractory disease should be monitored with continued TSH-suppression therapy. For inoperable and progressive RAI-refractory disease, somatic mutations need to be identified because systemic therapy based on genetic mutation (e.g., fusion-directed therapy) can be an effective treatment option [2].

The 2024 KTA pediatric guideline will be helpful in real-world clinical practice and will be updated to suit the domestic situation as needed.

Supplementary materials

Supplementary Tables 1 is available at https://doi.org/10.6065/apem.2448296.148.

Supplementary Table 1. Recommendations for Korean Thyroid Association Pediatric Thyroid Cancer Management Guideline

apem-2448296-148-Supplementary-Table-1.pdf

Notes

Conflicts of interest

No potential conflict of interest relevant to this article was reported.

Funding

This research was supported by a grant of Patient- Centered Clinical Research Coordinating Center (PACEN) funded by the Ministry of Health & Welfare, Republic of Korea (grant number: 2432240) and by research funding from the National Cancer Center (Grant Number 2112570).

References

1. Lee YA, Yun HR, Lee J, Moon H, Shin CH, Kim SG, et al. Trends in pediatric thyroid cancer incidence, treatment, and clinical course in Korea during 2004-2016: a nationwide population-based study. Thyroid. 2021; 31:902–11.

2. Lee YA, Lee H, Im SW, Song YS, Oh DY, Kang HJ, et al. NTRK and RET fusion-directed therapy in pediatric thyroid cancer yields a tumor response and radioiodine uptake. J Clin Invest. 2021; 131:e144847.

3. Lee YA, Im SW, Jung KC, Chung EJ, Shin CH, Kim JI, et al. Predominant DICER1 pathogenic variants in pediatric follicular thyroid carcinomas. Thyroid. 2020; 30:1120–31.

4. Moon JE, Oh SW, Kang HC, Koo BS, Kim K, Kim SW, et al. Korean Thyroid Association guidelines on the management of differentiated thyroid cancers; Part V. Pediatric differentiated thyroid cancer 2024. Int J Thyroidol. 2024; 17:193–207.

5. Lebbink CA, Links TP, Czarniecka A, Dias RP, Elisei R, Izatt L, et al. 2022 European Thyroid Association Guidelines for the management of pediatric thyroid nodules and differentiated thyroid carcinoma. Eur Thyroid J. 2022; 11:e220146.

6. Francis GL, Waguespack SG, Bauer AJ, Angelos P, Benvenga S, Cerutti JM, et al. Management guidelines for children with thyroid nodules and differentiated thyroid cancer. Thyroid. 2015; 25:716–59.

7. Sugino K, Nagahama M, Kitagawa W, Ohkuwa K, Uruno T, Matsuzu K, et al. Risk stratification of pediatric patients with differentiated thyroid cancer: is total thyroidectomy necessary for patients at any risk? Thyroid. 2020; 30:548–56.

8. Nies M, Vassilopoulou-Sellin R, Bassett RL, Yedururi S, Zafereo ME, Cabanillas ME, et al. Distant metastases from childhood differentiated thyroid carcinoma: clinical course and mutational landscape. J Clin Endocrinol Metab. 2021; 106:e1683. –97.

Fig. 1.

Initial treatment and follow-up strategy based on the postoperative 3-tier Pediatric Risk Classification. TSH, thyroid-stimulating hormone; US, ultrasound; SPECT, single-photon emission computed tomography; CT, computed tomography; Tg, thyroglobulin.

Table 1.

Hereditary tumor syndrome associated with thyroid tumor

Variable	DICER1 syndrome	PTEN hamartoma tumor syndrome	Carney complex	Familial adenomatous polyposis	Werner syndrome
Germline variant	DICER1 (14q32.13)	PTEN (10q23)	PRKAR1A(17q24.2)	APC (5q21-q22)	WRN (8p12)
Germline variant	DICER1 (14q32.13)	PTEN (10q23)	CNC2 (2p16)	APC (5q21-q22)	WRN (8p12)
Mode of inheritance	AD	AD	AD	AD	AR
Mode of inheritance	AD	>10% de novo	30% de novo	20% de novo	AR
Type of thyroid tumor	Multinodular goiter, follicular adenoma, follicular thyroid cancer, papillary thyroid cancer, and poorly differentiated carcinoma	Multinodular goiter, follicular adenoma, follicular thyroid cancer, and papillary thyroid cancer	Multinodular goiter, follicular adenoma, follicular thyroid cancer, and papillary thyroid cancer	Papillary thyroid cancer (Cribriformmorular cancer)	Papillary thyroid cancer, follicular thyroid cancer, and anaplastic thyroid cancer
Thyroid tumor frequency	7%	10%–30%	4%–10%	2%–12%	18%
Clinical phenotype	Macrocephaly	Macrocephaly, learning difficulties, autism and developmental delay, lipomas, vascular features including hemangiomas and arteriovenous malformations, gingival hypertrophy, oral papillomas, facial papules, acral keratoses, palmoplantar keratosis, trichilemmomas, pigmented macules of the glans penis, and overgrowth of tissues	Pale brown to black lentigines of skin, lips, and oral mucosa, soft tissue myxomas, Schwannomas, and epithelioid-type blue nevi	Congenital hypertrophy of the retinal pigment epithelium, congenital absence of teeth, delayed eruption of teeth, dentigerous cysts, supernumerary teeth, odontomas, epidermoid cysts, fibrous dysplasia of the skull, mandibular osteomas, fibromas, desmoid tumors, and pilomatricomas	Short stature (lack of pubertal growth spurt), cataracts, premature aging, tight atrophic skin, ulceration, hyperkeratosis, pigmentary alterations, regional subcutaneous atrophy, and characteristic ‘bird-like facies,’ hypogonadism, secondary sexual underdevelopment, premature greying and thinning of scalp hair, pes planus, and abnormal voice
Additional tumors	Pleuropulmonary blastoma, ovarian Sertoli-Leydig cell tumors, cystic nephroma, body medulloepithelioma, botryoid - type embryonal rhabdomyosarcoma, nasal chondromesenchymal hamartoma, pituitary blastoma, pineoblastoma, Wilms tumor, juvenile intestinal hamartomas	Benign and malignant tumors of the breast, colon, endometrium, and kidney, adult Lhermitte-Duclos disease due to cerebellar dysplastic gangliocytoma	Benign adrenal tumors (primary pigmented nodular adrenocortical disease), pituitary tumors, large cell calcified Sertoli cell tumors, breast ductal adenoma, osteochondromyxoma, psammomatous melanotic Schwannoma of the nerve sheath	Hepatoblastoma, medulloblasroma, multiple adenomatous polyps GI	Malignant melanoma, meningioma, soft tissue sarcomas, leukemia and pre-leukemic conditions of the bone marrow, primary bone neoplasm, osteoporosis, soft tissue calcification, evidence of premature atherosclerosis

AD, autosomal dominant; AR, autosomal recessive; GI, gastrointestinal.

This table is based on the 2015 ATA Pediatric Guidelines [6] and 2022 ETA Pediatric Guidelines. [5]