Practice Essentials
Although the literature contains numerous reports on pediatric thyroid carcinoma, the low incidence and subsequent lack of prospective randomized trials have made drawing absolute conclusions regarding the definitive workup, management, and treatment of this disease difficult. In 2015, however, a task force commissioned by the American Thyroid Association (ATA), following an extensive literature search, issued the first guidelines on the management of pediatric thyroid nodules and differentiated thyroid cancer. [1, 2] Nevertheless, 2022 guidelines from the European Thyroid Association noted that for many questions on management of pediatric thyroid carcinoma, little or no evidence was available. [3]
All guidelines stress that management of pediatric thyroid cancer should be provided by multidisciplonary teams that include highly experienced thyroid surgeons, at institutions with a full range of pediatric and oncologic resources. [1, 3]
A detailed understanding of how to perform a comprehensive evaluation of thyroid nodules and persistent cervical adenopathy in pediatric patients is necessary in order to establish the diagnosis of pediatric thyroid cancer. Although thyroid nodules are far less common in children than in adults—with a prevalence rate of 0.2-5%, compared with approximately 30% in adults—pediatric thyroid nodules carry a far greater risk of harboring malignancy: Cancer is found in 22-26% of thyroid nodules in pediatric patients (some authors have reported a cancer incidence as high as 36%) compared with 5-10% in adults. [1, 4] Because of this increased risk of malignancy, pediatric thyroid nodules require an expeditious workup. [5, 6]
Radiation exposure, which is still used either as therapy prior to hematopoietic stem cell transplantation or as a treatment of Hodgkin lymphoma, remains a major risk factor for pediatric thyroid cancer. [7] Multiple endocrine neoplasia type 2 (MEN2) causes medullary thyroid cancer in children. [2] Other risk factors for pediatric thyroid cancer include autoimmune thyroiditis and rare familial cancer syndromes such as APC-associated polyposis and Carney complex. [2] See Etiology for more detail.
Despite the fact that pediatric thyroid cancer usually presents at an advanced stage, it carries an excellent prognosis, with 10-year survival rates greater than 98%. [3]
Signs and symptoms
Thyroid carcinoma in pediatric patients usually manifests as an asymptomatic neck mass. [2] A painless noninflammatory metastatic cervical mass is the presenting sign in 40-80% of patients. [8] The neck masses are typically discovered incidentally by parents or patients or by physicians during routine physical examination. Only about 50% of children with thyroid carcinoma present with nodular thyroid enlargement as the presenting symptom. Cervical lymphadenopathy is present in approximately a third of cases. [9] Vocal cord paralysis in children with thyroid malignancy is much less common than in adults with thyroid malignancy. [10]
Additionally, unlike adults, young patients with thyroid nodules often do not report pain, tenderness, compression of the respiratory tract, problems with swallowing, or inappropriate fixation of the neck. Even young patients who have lung metastases usually do not report pulmonary symptoms. [11] Approximately 2% of pediatric thyroid cancer patients present with metastasis to the lungs, and 1% with metastasis to bones. [9]
Workup
The recommended diagnostic protocol of thyroid nodules consists of the following steps:
- History (including famy history of cancer and personal history of radiation exposure) and physical examination
- Laboratory tests, including thyroid-stimulating hormone (TSH) and thyroglobulin levels
- Thyroid ultrasonography
- Fine-needle aspiration biopsy (FNAB)
Molecular marker analysis of FNAB samples has been used to identify oncogenic mutations of concern, the presence or absence of which might sway the argument for total thyroidectomy versus lobectomy. However, evidence in support of this practice is lacking. [2, 3] For example, presence of a BRAF V600E mutation in a thyroid nodule indicates high risk of malignancy, but this finding requires confirmation, such as by frozen section during thyroid surgery. [2, 3]
Scintigraphy has only a limited role. When TSH is suppressed, scintigraphy demonstrating the functional hyperactivity of a thyroid nodule confirms the diagnosis of an autonomous thyroid nodule. [1, 2, 3]
Management
Treatment for thyroid malignancy is primarily surgical. Lobectomy may be considered for solitary lower-risk cancers (eg, follicular neoplasms without concerning mutations), but total thyroidectomy, with or without central neck dissection, is typically recommended for lesions that are malignant or suspicious for malignancy. [2] For most children with papillary thyroid cancer, total thyroidectomy is recommended; for children with biopsy-proven medullary carcinoma , total thyroidectomy and central neck dissection are indicated. Total thyroidectomy may be associated with improved rates of disease- and recurrence-free survival. [3]
Radioactive therapy with iodine 131 (131I) has traditionally been used after thyroidectomy in pediatric patients, to ablate residual normal thyroid and to treat functioning metastases in differentiated thyroid tumors. Because pediatric patients are few and the prognosis is generally excellent, 131I is usually recommended only for patients with extensive unresectable cervical nodal involvement, invasion of vital structures, or distant metastases.
Selpercatinib is the first targeted therapy to be approved by the US Food and Drug Administration (FDA) for tumors that have rearranged-during-transfection (RET) mutations. It is indicated for children aged 12 years or older with advanced or metastatic RET fusion–positive thyroid cancer who require systemic therapy and whose cancer (if radioactive iodine is appropriate) is refractory to radioactive iodine. Selpercatinib is also indicated for children aged 12 years or older in whom advanced or metastatic RET-mutant medullary thyroid cancer requires systemic therapy. [12]
See Treatment for more information.
Etiology
Thyroid carcinoma is a known sequela of radiation exposure. From the 1920s to the 1960s, external beam radiation was used for treatment of benign lesions (eg, tinea capitis, tonsillar hypertrophy, acne, thymic enlargement, hemangiomas) prior to recognition of its carcinogenic effects. [13, 14, 15, 16, 17] The Chernobyl disaster in 1986 caused up to a 100-fold increase in the incidence of pediatric thyroid carcinoma in the exposed population. Cases associated with radiation exposure are mostly papillary carcinoma, and those in residents of iodine-deficient areas are more likely follicular. [16, 18, 11]
Radiation therapy and chemotherapy for other pediatric malignancies also have been implicated in thyroid malignancy. Children who undergo radiation therapy prior to hemoatopoietic stem cell transplantation and children who undergo primary radiation treatments for Hodgkin lymphoma are at increased risk for thyroid cancer. [13, 15] The risk for thyroid cancer is dose dependent. [19]
Congenital hypothyroidism (CH), due to either dyshormonogenesis or an iodine transporter defect, increases the risk of thyroid nodules. Chronic thyroid-stimulating hormone (TSH) elevation increases the risk of neoplastic transformation of thyroid. The benign nodules usually respond to thyroxine treatment. Those that remain or enlarge despite suppression therapy should undergo biopsy. [20]
Thyroglossal duct cysts, the most common developmental thyroid anomaly, carry an increased, albeit small, risk of malignant transformation, estimated to be 1%. [21] This is one of the reasons excision with the Sistrunk procedure (removal of cyst, central hyoid bone, and core from the base of the tongue) is recommended.
Epidemiology
Frequency
United States
Thyroid cancer, the most common pediatric endocrine neoplasm, represents 3% of all pediatric malignancies and 5-5.7% of malignancies in the head and neck. Only 5% of all thyroid cancers occur in children and adolescents. [22] Thyroid nodules occur in up to 35% of the general adult population but in only 1-2% of the pediatric population. These numbers are estimated using a compilation of data from multiple reports. [7, 23, 24]
Despite the lower incidence of thyroid nodules in children, a pediatric thyroid nodule has a greater risk of containing or developing a malignancy. Whereas 5% of nodules in adults are malignant, in the pediatric population the percentage of malignant nodules is 26.4%. [10] The incidence of malignancy in multinodular goiter is 1-7% and is 10-25% in solitary nodules. [7] Pediatric thyroid cancer (3% prevalence) in adolescents is also associated with juvenile autoimmune thyroiditis. [25]
A study by Bernier et al found that in the United States between 1998 and 2013, the rate of pediatric differentiated thyroid cancer significantly increased among individuals aged 0 to 19 years, rising by 4.43% per year. This increase was seen in both sexes, with the rates rising in non-Hispanic whites, non-Hispanic blacks, and Hispanics. With regard to cancer stage, the annual rate increases for localized, regional, and distant tumors were 4.06%, 5.68%, and 8.55%, respectively, with the yearly increases for tumors less than 1 cm, 1-2 cm, and over 2 cm in size being 9.46%, 6.92%, and 4.69%. Owing to the climb in large and late-stage differentiated thyroid cancer rates, the investigators suggested that improved medical surveillance cannot entirely account for the changes. [26]
Using the US Cancer Statistics database, a study by Siegel et al found that the overall incidence of pediatric thyroid carcinoma in the United States increased between 2003 and 2019, with an average annual percentage change (AAPC) of 4.2%. In adolescents (ages 15-19 years), thyroid carcinoma was one of the most common of the International Classification of Childhood Cancer (ICCC) types, with a rate of 25.9 per million population (age adjusted to the 2000 US standard population) and an AAPC of 4.5%. The investigators suggested that the rise in pediatric thyroid carcinoma may have derived from overdiagnosis in addition to an actual increase in incidence stemming from various causes (eg, environmental exposures, such as ionizing radiation). [27]
Papillary thyroid cancer is by far the common thyroid malignancy in children, constituting 83% of all pediatric thyroid malignancies. [28] Although papillary carcinoma is more aggressive in children than in adults, pediatric papillary cancer carries a much better prognosis that adult thyroid cancer. [29]
Medullary thyroid cancer (MTC), which constitutes 5% of pediatric thyroid malignancies, is usually associated with multiple endocrine neoplasia type 2 (MEN2) in the pediatric population. The inheritance pattern occurs either sporadically or as familial MTC without other associated endocrine abnormalities. MEN2 consists of MTC and pheochromocytoma and either hyperparathyroidism (MEN2A) or mucosal neuromas (MEN2B). MTC associated with MEN2B is more virulent and may occur and metastasize early in infancy.
International
After the Chernobyl nuclear power plant disaster in 1986, individuals living in Russia, Ukraine, and eastern Europe were exposed to significant levels of radioactive iodines, primarily iodine 131 (131I). This radioactivity, which is concentrated in the thyroid gland, resulted in a substantial increase in pediatric thyroid cancer rates among this cohort of children. [30, 31]
Mortality/morbidity
Pediatric thyroid malignancies are usually a well-differentiated papillary subtype or the papillary-follicular subtype, but all histologic types have been observed. Children commonly present with advanced disease. At presentation, 70% of patients have extensive regional nodal involvement, and 10-20% of patients have distant metastasis. [32] The lungs are the most common sites of metastasis.
Pediatric patients seem to have higher local and distant recurrence rates than adults, but they tend to respond rapidly to therapy. The prognosis for children is excellent, with mortality rates of less than 10%. [33] Benign tumors such as follicular adenomas should be considered at risk for transformation into follicular thyroid carcinoma, and they must be surgically addressed. [10]
A retrospective study by Gruszczynski et al found that although 2- and 5-year overall and disease-specific survival in pediatric thyroid cancer was close to 100% in the report’s patients, various factors—including male sex, non-White race, poverty, and language isolation—were associated with worse overall survival in these persons. Moreover, male and Black pediatric patients were more likely to present with a higher-stage disease. [34]
Sex
Thyroid carcinoma is more common in females, [35] but extent varies by patient age: In adults, the female:male ratio is 4:1; in individuals younger than 15 years, it is as low as 1.5:1, while in those aged 15–20 years, it is 3:1. [36] This implies that female sex hormones, especially during puberty, play a significant yet still undefined role in the increased incidence of thyroid cancer in females. [22]
Age
Age is a major determinant of both the incidence and recurrence of pediatric thyroid carcinoma. Pediatric thyroid carcinoma occurs more frequently in adolescents, although it has been reported in the neonatal period. [37] In children younger than 10 years, identified thyroid lesions are more likely to be malignant. [38] Children younger than 10 years are also more likely to have recurrent cancer. [33]
Prognosis
Unlike thyroid cancer in adults, in the pediatic population the degree of invasion and metastases does correspond to prognosis. Lymph node involvement does not affect the prognosis in children and adolescents. [22] This can be attributed to an overwhelming majority of well-differentiated cancers, low incidence of bone metastasis, and excellent response to radioactive iodine therapy. However, pediatric patients with radiation-induced thyroid cancer are at an increased risk for additional cancer later in life. [16]
Pediatric patients have higher local and distant recurrence rates than adults, but recurrences tend to respond rapidly to therapy. Some studies report young age as the major determinant of recurrence in pediatric differentiated thyroid carcinoma, which suggests a difference in tumor biology. The prognosis is excellent in children, with mortality rates of less than 10%. The overall 20-year survival rate is 92-100%.
Rearrangements in the RET protooncogene have been observed in persons exposed to radiation, with a reported RET rearrangement rate between 50% and 70%. [33] Williams et al studied Chernobyl-induced thyroid tumor behavior and found that thyroid tumors associated with the RET and PTC3 oncogenes were more aggressive, faster growing, and less differentiated. [30] Thyroid tumors with the RET/PTC1 oncogene had more benign characteristics and were slower growing.
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A monomorphous cell population of Hürthle cells arranged in loosely cohesive clusters and single cells. The cells are polyhedral and have abundant granular cytoplasm with well-defined cell borders. The nuclei are enlarged and have a central prominent macronucleolus.
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