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Incidence
In the United States, the annual incidence of thyroid cancers is 10.7 cases per 1 million in people aged 0 to 19 years. The incidence is higher in females than in males (17.6 vs. 4.1 cases per 1 million people, respectively) and lower in Black people than in White people (3.9 vs. 11.8 cases per 1 million people, respectively). It accounts for approximately 6% of all cancers in this age group.[
Two time-trend studies using the Surveillance, Epidemiology, and End Results (SEER) Program database have shown a 2% and 3.8% annual increase in the incidence of differentiated thyroid carcinoma in the United States among children, adolescents, and young adults in the 1973 to 2011 and 1984 to 2010 periods, respectively.[
The papillary subtype is the most common subtype of childhood thyroid cancer, accounting for approximately 60% of cases, followed by the papillary follicular variant subtype (20%–25%), the follicular subtype (10%), and the medullary subtype (<10%). The anaplastic subtype occurs in less than 1% of pediatric thyroid carcinomas. The incidence of the papillary subtype and its follicular variant peaks between the ages of 15 and 19 years. The incidence of medullary thyroid cancer is the highest in children aged 0 to 4 years and declines at older ages (see
Figure 1. Incidence of pediatric thyroid carcinoma based on most frequent subtype per 100,000 as a percent of total cohort. Reprinted from International Journal of Pediatric Otorhinolaryngology, Volume 89, Sarah Dermody, Andrew Walls, Earl H. Harley Jr., Pediatric thyroid cancer: An update from the SEER database 2007–2012, Pages 121–126, Copyright (2016), with permission from Elsevier.
Diagnostic Evaluation
The prevalence of benign thyroid nodules in childhood has been estimated at about 0.5% to 2%.[
FNA results are categorized according to the six tiers of The Bethesda System for Reporting Thyroid Cytopathology (see
Bethesda Category | Cytopathological Category | Malignancy Rate | Suggested Treatment |
---|---|---|---|
FNA = fine-needle aspiration; US = ultrasonography. | |||
a Reprinted from |
|||
I | Nondiagnostic/inadequate | 1%–5% | Repeat FNA (other options: continued US surveillance, lobectomy) |
II | Benign | 0%–10% | Serial US if small, lobectomy if >4 cm |
III | Atypia/follicular lesion of undetermined significance | 0%–44% | Molecular genetics, lobectomy if no concerning mutation, thyroidectomy ifBRAFor fusion mutation |
IV | Follicular neoplasm | 60%–71% | Molecular genetics, lobectomy if no concerning mutation, thyroidectomy ifBRAFor fusion mutation |
V | Suspicious for malignancy | 70%–86% | Total thyroidectomy +/− central neck dissection |
VI | Malignant | 97%–100% | Total thyroidectomy +/− central neck dissection |
While molecular testing of thyroid nodules could be helpful in the diagnosis of papillary thyroid carcinoma, there is no evidence to support its use.[
Figure 2. Flowchart showing the initial evaluation, treatment, and follow-up of pediatric thyroid nodules. #The expert panel suggests considering the measurement of serum calcitonin in children suspect of medullary thyroid carcinoma (MTC) based on individual conditions and the preference of the physician (Recommendation 5A). The expert panel suggests that, in selected cases (conditions that suggest MEN2, a positive family history of MEN2, or in case of bulky thyroid disease), the measurement of calcitonin may be of additional value for early diagnosis of MTC (Recommendation 5B). *Malignancy risk (suspicious vs. no suspicion) is based on neck ultrasound characteristics (described in section B2. Risk of malignancy in a thyroid nodule during childhood), history of radiation, and signs of a pre-disposition syndrome. If there is a significant increase in nodule size or the ultrasound characteristics change over time, repeated fine-needle biopsy (FNB) should be performed. **Analysis of the presence of other oncogenic drivers and gene fusions (e.g., RET/PTC and NTRK fusions) may be considered in Bethesda 3, 4, or 5 due to increasing awareness that these are also associated with the presence of papillary thyroid carcinoma (PTC). In case a BRAF V600E mutation is found, the risk of the thyroid nodule being malignant is high but needs to be confirmed, for example, by frozen section during thyroid surgery. ^Total thyroidectomy after proven presence of MTC. ^^Alternatively, FNB can be performed; in case of differentiated thyroid carcinoma (DTC), a total thyroidectomy should be performed. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Credit: Lebbink, C. A., Links, T. P., Czarniecka, A., Dias, R. P., Elisei, R., Izatt, L., Krude, H., Lorenz, K., Luster, M., Newbold, K., Piccardo, A., Sobrinho-Simões, M., Takano, T., Paul van Trotsenburg, A. S., Verburg, F. A., & van Santen, H. M. (2022). 2022 European Thyroid Association Guidelines for the management of pediatric thyroid nodules and differentiated thyroid carcinoma. European Thyroid Journal, 11(6), e220146. Retrieved Aug 2, 2024, from https://doi.org/10.1530/ETJ-22-0146.
References:
Risk Factors
Risk factors for pediatric differentiated thyroid cancer include the following:
Papillary thyroid carcinoma is the most frequent form of thyroid carcinoma diagnosed after radiation exposure.[
Clinical Presentation and Prognostic Factors
Patients with thyroid cancer usually present with a thyroid mass with or without painless cervical adenopathy.[
In well-differentiated thyroid cancer, male sex, larger tumor size, and distant metastases have been found to have prognostic significance for early mortality. However, even patients in the highest risk group who had distant metastases had a 90% survival rate.[
In addition, the following observations have been reported:
A review of the National Cancer Database found that patients aged 21 years and younger from lower-income families and those lacking insurance experienced a longer period from diagnosis to treatment of their well-differentiated thyroid cancer and presented with higher-stage disease.[
A single-institution retrospective review analyzed the impact of multifocal disease at presentation for patients with papillary thyroid carcinoma.[
A single-institution study compared diagnostic whole-body 131I scans with stimulated thyroglobulin (sTg) levels as predictors of distant metastasis in children with papillary thyroid carcinoma.[
Histology and Molecular Features of Differentiated Thyroid Cancer
Tumors of the thyroid are classified as adenomas or carcinomas.[
Histology
Papillary and follicular carcinomas are often referred to as differentiated thyroid carcinoma. The pathological classification of differentiated thyroid carcinomas is based on standard definitions set by the World Health Organization, and the criteria are the same for children and adults. Long-term outcomes for children and adolescents with differentiated thyroid carcinoma are excellent, with 10-year survival rates exceeding 95%.[
Molecular features
Thyroid tumorigenesis and progression of thyroid carcinomas of follicular cells (differentiated thyroid carcinoma, poorly differentiated papillary thyroid carcinoma, and anaplastic thyroid carcinoma) are defined by a multistep process that results in aberrant activation of the MAPK and/or PI3K/PTEN/AKT signaling pathways. Comprehensive genomic studies performed over the last decade have defined the landscape of these tumors, as well as their genotype-phenotype correlations. Using advanced sequencing technologies, oncogenic alterations are found in more than 90% of tumors.[
Variants in BRAF and RAS genes are the most common drivers, followed by gene fusions involving RET or NTRK:[
The presence of BRAF V600E has been associated with extrathyroidal tumor extension and an increased risk of recurrence. However, its prognostic significance is controversial. BRAF V600E tumors appear to show a broadly immunosuppressive profile with high expression of anti–programmed death-ligand 1 (PD-L1).[
A retrospective analysis of 80 Brazilian patients younger than 18 years with papillary thyroid carcinoma identified AGK::BRAF fusions and BRAF V600E single nucleotide variants.[
A retrospective review identified 113 RET fusion–positive tumors among 993 patients with papillary thyroid carcinoma.[
A study correlated the status of hotspot DICER1 variants with clinical, histological, and outcome features in a series of 56 pediatric patients with papillary thyroid carcinomas. These patients had no clinical or family history of DICER1-related syndromic manifestations.[
A study profiled miRNA in 20 non-neoplastic thyroid tissue specimens, 8 adenomatous specimens, and 60 pediatric thyroid cancer specimens, 8 of which had DICER1 RNase IIIb variants. All differentiated thyroid cancers with DICER1 variants were follicular. Six were follicular variant papillary thyroid cancers, and two were follicular thyroid cancers.[
Other alterations include the following:[
The spectrum of somatic genetic alterations seems to differ between pediatric and adult patients when analyzing tumors with similar histologies, as follows:[
Treatment of Papillary and Follicular Thyroid Carcinoma
Treatment options for papillary and follicular (differentiated) thyroid carcinoma include the following:
In 2015, the American Thyroid Association (ATA) Task Force on Pediatric Thyroid Cancer published guidelines for the management of thyroid nodules and differentiated thyroid cancer in children and adolescents. The guidelines (summarized below) are based on scientific evidence and expert panel opinion, with a careful assessment of the level of evidence.[
Preoperative evaluation
Preoperative evaluation factors to consider include the following:
Surgery
Total thyroidectomy is the cornerstone of the management of differentiated thyroid carcinoma. Pediatric thyroid surgery is ideally completed by a surgeon who has experience performing endocrine procedures in children and in a hospital with the full spectrum of pediatric specialty care. The ATA recommends that the thyroidectomy be performed by an experienced thyroid surgeon (>30 cases/year) or as a multidisciplinary approach between a pediatric surgeon and an adult endocrine or head and neck surgeon.[
Thyroidectomy
For patients with papillary or follicular carcinoma, total thyroidectomy is the recommended treatment. The ATA expert panel recommendation is based on data showing an increased incidence of bilateral (30%) and multifocal (65%) disease.[
In patients with a small unilateral tumor confined to the gland, a near-total thyroidectomy—in which a small amount of thyroid tissue (<1%–2%) is left in place at the entry point of the recurrent laryngeal nerve or superior parathyroid glands—might be considered to decrease permanent damage to those structures.[
A retrospective analysis identified factors associated with bilateral thyroid involvement in 115 pediatric patients with well-differentiated thyroid cancer.[
Another multicenter retrospective analysis evaluated the prevalence of and risk factors for multifocal disease in 212 pediatric patients with papillary thyroid carcinoma.[
Thyroid resections that are less than a total thyroidectomy are associated with up to tenfold greater recurrence rates. Total thyroidectomy also optimizes the use of radioactive iodine for imaging and treatment.
Central neck dissection
A therapeutic central neck lymph node dissection (level VI nodes) should be done in the presence of clinical evidence of central or lateral neck metastases.[
For patients without clinical evidence of gross extrathyroidal invasion or locoregional metastasis, a prophylactic central neck dissection may be considered based on tumor focality and primary tumor size. However, because of the increased morbidity associated with central lymph node dissection, it is important to consider the risks and benefits of the extent of dissection on a case-by-case basis.[
Lateral neck dissection
Modified radical neck dissection is reserved for biopsy-proven metastatic disease in the lateral compartment (levels II, III, IV, and V). Cytological confirmation of metastatic disease to lymph nodes in the lateral neck is recommended before surgery.
Routine prophylactic lateral neck dissection is not recommended.
Figure 3. Flowchart showing the surgical approach for differentiated thyroid carcinoma (DTC) in children. BCLND, bilateral central lymph node dissection; CLND, central lymph node dissection; FNB, fine needle biopsy; ICLND, ipsilateral central lymph node dissection. ‘Active surveillance' in low-risk DTC implies ultrasound of the leftover thyroid tissue, including the evaluation of the cervical lymph nodes every 6–12 months by neck palpation and ultrasound. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Credit: Lebbink, C. A., Links, T. P., Czarniecka, A., Dias, R. P., Elisei, R., Izatt, L., Krude, H., Lorenz, K., Luster, M., Newbold, K., Piccardo, A., Sobrinho-Simões, M., Takano, T., Paul van Trotsenburg, A. S., Verburg, F. A., & van Santen, H. M. (2022). 2022 European Thyroid Association Guidelines for the management of pediatric thyroid nodules and differentiated thyroid carcinoma. European Thyroid Journal, 11(6), e220146. Retrieved Aug 2, 2024, from https://doi.org/10.1530/ETJ-22-0146.
Classification and risk assignment
Despite the limited data in pediatrics, the ATA Task Force recommends the use of the tumor-node-metastasis (TNM) classification system to categorize patients into one of three risk groups.[
For more information about the TNM system, see the
Postoperative staging and long-term surveillance
After surgical resection, disease is staged based on the operative findings to identify patients with persistent disease and those at intermediate or high risk of recurrence. Initial staging should be performed within 12 weeks after surgery to assess for evidence of persistent locoregional disease and to identify patients who are likely to benefit from additional therapy with 131I. The ATA pediatric risk level helps determine the extent of postoperative testing.[
ATA pediatric low risk
ATA pediatric intermediate risk
ATA pediatric high risk
For patients with antithyroglobulin antibodies, deferred postoperative staging to allow time for antibody clearance, except in patients with T4 or M1 disease.
Radioactive iodine ablation (RAI)
The goal of 131I therapy is to decrease recurrence and mortality by eliminating iodine-avid disease.[
While rare, late effects of 131I treatment include salivary gland dysfunction, bone marrow suppression, pulmonary fibrosis, and second malignancies.[
Evidence (RAI):
The ETA has proposed a simplified follow-up plan based on thyroglobulin levels and neck ultrasonography (see
Figure 4. Flowchart showing the follow-up of children with differentiated thyroid carcinoma (DTC) who achieved complete remission after initial treatment with total thyroidectomy and I-131. This flowchart was developed for children with DTC who achieved complete remission defined as: undetectable levels of serum thyroglobulin (Tg) on levothyroxine (LT4), undetectable levels of Tg antibodies, negative neck ultrasound, and if performed, negative whole-body scan 1 year after last treatment. ^In the first year until clinical remission, TSH levels should be suppressed, while a normal low value of TSH (between 0.5 and 1.0 mIU/L) will be advisable thereafter. ^^The definition of consistently rising Tg on LT4 is debatable; the levels of Tg as well as the doubling time should be taken into account and weighted in the individual patient. *The expert panel suggests that, in children with detectable (but not rising) Tg and no focus on neck ultrasound, I-123 scanning may be considered in individual cases. When both ultrasound and radioiodine imaging did not yield a focus, FDG PET/CT may be considered. This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License. Credit: Lebbink, C. A., Links, T. P., Czarniecka, A., Dias, R. P., Elisei, R., Izatt, L., Krude, H., Lorenz, K., Luster, M., Newbold, K., Piccardo, A., Sobrinho-Simões, M., Takano, T., Paul van Trotsenburg, A. S., Verburg, F. A., & van Santen, H. M. (2022). 2022 European Thyroid Association Guidelines for the management of pediatric thyroid nodules and differentiated thyroid carcinoma. European Thyroid Journal, 11(6), e220146. Retrieved Aug 2, 2024, from https://doi.org/10.1530/ETJ-22-0146.
Treatment of Recurrent Papillary and Follicular Thyroid Carcinoma
Despite having more advanced disease at presentation than adults, children with differentiated thyroid cancer generally have an excellent survival with relatively few side effects.[
Treatment options for recurrent papillary and follicular thyroid carcinoma include the following:
RAI with 131I
RAI with 131I is usually effective after recurrence.[
Tyrosine kinase inhibitors (TKIs)
For patients with 131I-refractory disease, molecularly targeted therapies using TKIs may provide alternative therapies.
TKIs with documented efficacy for the treatment of adults include the following:
Pediatric-specific data are limited. However, in one case report, sorafenib produced a radiographic response in a patient aged 8 years with metastatic papillary thyroid carcinoma.[
Three children with papillary thyroid carcinoma who were refractory to radioactive iodine had a clinical response to lenvatinib.[
For more information, see
Treatment options under clinical evaluation for recurrent papillary and follicular thyroid carcinoma
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
References:
Medullary thyroid carcinoma is a rare form of thyroid carcinoma that originates from calcitonin-secreting parafollicular C cells and accounts for less than 10% of all cases of thyroid carcinoma in children.[
Risk Factors
In children, medullary thyroid carcinoma is usually associated with RET germline pathogenic variants in the context of multiple endocrine neoplasia type 2 (MEN2) syndrome.[
A single-institution study retrospectively analyzed 144 patients aged 21 years or younger with medullary thyroid carcinoma presenting between 1961 and 2019.[
Clinical Presentation and Prognostic Factors
Children with thyroid cancer usually present with a thyroid mass with or without painless cervical adenopathy.[
Children with medullary thyroid carcinoma present with an aggressive clinical course; 50% of patients have hematogenous metastases at diagnosis.[
A review of 430 patients aged 0 to 21 years with medullary thyroid cancer reported that worse prognosis was associated with older age (16–21 years) at diagnosis, tumor diameter greater than 2 cm, positive margins after total thyroidectomy, and lymph node metastases.[
From 1997 to 2019, the German Society for Pediatric Oncology and Hematology–Malignant Endocrine Tumors registry identified a total of 57 patients with medullary thyroid carcinoma and 17 patients with C-cell hyperplasia.[
In children with hereditary MEN2B, medullary thyroid carcinoma may be detectable within the first year of life, and nodal metastases may occur before age 5 years. The recognition of mucosal neuromas, a history of alacrima, constipation (secondary to intestinal ganglioneuromatosis), and marfanoid facial features and body habitus is critical to early diagnosis because the RET M918T variant associated with MEN2B is often de novo. Approximately 50% of patients with MEN2B develop a pheochromocytoma. There is a varying degree of risk of developing pheochromocytoma and hyperparathyroidism in MEN2A, based on the specific RET variant.[
The National Cancer Institute is conducting a natural history study of children and young adults with medullary thyroid cancer (NCT01660984).
For more information, see
Histology and Molecular Features of Medullary Thyroid Cancer
Tumors of the thyroid are classified as adenomas or carcinomas.[
Medullary thyroid carcinoma is a neuroendocrine malignancy derived from the neural crest-originated parafollicular C cells of the thyroid gland. In children, medullary thyroid carcinoma is a monogenic disorder caused by a dominantly inherited or de novo gain-of-function variant in the RET proto-oncogene associated with either MEN2A or MEN2B, depending on the specific variant.[
Treatment of Medullary Thyroid Carcinoma
Medullary thyroid carcinomas are commonly associated with the MEN2 syndrome. For more information, see
Treatment options for medullary thyroid carcinoma include the following:
Surgery
Treatment for children with medullary thyroid carcinoma is mainly surgical. Investigators have concluded that prophylactic central node dissection should not be performed on patients with hereditary medullary thyroid cancer if their basal calcitonin serum levels are lower than 40 pg/mL.[
Most cases of medullary thyroid carcinoma in children occur in the context of the MEN2A and MEN2B syndromes. In those familial cases, early genetic testing and counseling is indicated, and prophylactic surgery is recommended for children with the RET germline pathogenic variant. Strong genotype-phenotype correlations have facilitated the development of guidelines for intervention, including screening and age at which prophylactic thyroidectomy should occur.[
Evidence (surgery):
The American Thyroid Association has proposed the following guidelines for prophylactic thyroidectomy in children with hereditary medullary thyroid carcinoma (see
| Medullary Thyroid Carcinoma Risk Level | ||
---|---|---|---|
| Highest (MEN2B) | High (MEN2A) | Moderate (MEN2A) |
MEN2A = multiple endocrine neoplasia type 2A; MEN2B = multiple endocrine neoplasia type 2B. | |||
a Adapted from Wells et al.[ |
|||
RET Variant | M918T | A883F, C634F/G/R/S/W/Y | G533C, C609F/G/R/S/Y, C611F/G/S/Y/W, C618F/R/S, C620F/R/S, C630R/Y, D631Y, K666E, E768D, L790F, V804L, V804M, S891A, R912P |
Age for Prophylactic Thyroidectomy | Total thyroidectomy in the first year of life, ideally in the first months of life. | Total thyroidectomy at or before age 5 y based on serum calcitonin level. | Total thyroidectomy to be performed when the serum calcitonin level is above the normal range or at convenience if the parents do not wish to embark on a lengthy period of surveillance. |
Tyrosine kinase inhibitor (TKI) therapy
A number of TKIs have been evaluated and approved for patients with advanced medullary thyroid carcinoma.
Children with locally advanced or metastatic medullary thyroid carcinoma were treated with vandetanib in a phase I/II trial. Of 16 patients, only 1 had no response, and 7 had partial responses, for an objective response rate of 44%. Disease in three of those patients subsequently recurred, but 11 of 16 patients treated with vandetanib remained on therapy at the time of the report. The median duration of therapy for the entire cohort was 27 months, with a range of 2 to 52 months.[
For more information, see
Treatment options under clinical evaluation for medullary thyroid carcinoma
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
References:
Cancer in children and adolescents is rare, although the overall incidence has slowly increased since 1975.[
For specific information about supportive care for children and adolescents with cancer, see the summaries on
The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of children and adolescents with cancer.[
Dramatic improvements in survival have been achieved for children and adolescents with cancer. Between 1975 and 2020, childhood cancer mortality decreased by more than 50%.[
Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years.[
The designation of a rare tumor is not uniform among pediatric and adult groups. In adults, rare cancers are defined as those with an annual incidence of fewer than six cases per 100,000 people. They account for up to 24% of all cancers diagnosed in the European Union and about 20% of all cancers diagnosed in the United States.[
Most cancers in subgroup XI are either melanomas or thyroid cancers, with other cancer types accounting for only 2% of the cancers diagnosed in children aged 0 to 14 years and 9.3% of the cancers diagnosed in adolescents aged 15 to 19 years.
These rare cancers are extremely challenging to study because of the relatively few patients with any individual diagnosis, the predominance of rare cancers in the adolescent population, and the small number of clinical trials for adolescents with rare cancers.
Information about these tumors may also be found in sources relevant to adults with cancer, such as
References:
The PDQ cancer information summaries are reviewed regularly and updated as new information becomes available. This section describes the latest changes made to this summary as of the date above.
This summary was reformatted.
This summary is written and maintained by the
Purpose of This Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of childhood thyroid cancer. It is intended as a resource to inform and assist clinicians in the care of their patients. It does not provide formal guidelines or recommendations for making health care decisions.
Reviewers and Updates
This summary is reviewed regularly and updated as necessary by the
Board members review recently published articles each month to determine whether an article should:
Changes to the summaries are made through a consensus process in which Board members evaluate the strength of the evidence in the published articles and determine how the article should be included in the summary.
The lead reviewers for Childhood Thyroid Cancer Treatment are:
Any comments or questions about the summary content should be submitted to Cancer.gov through the NCI website's
Levels of Evidence
Some of the reference citations in this summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Pediatric Treatment Editorial Board uses a
Permission to Use This Summary
PDQ is a registered trademark. Although the content of PDQ documents can be used freely as text, it cannot be identified as an NCI PDQ cancer information summary unless it is presented in its entirety and is regularly updated. However, an author would be permitted to write a sentence such as "NCI's PDQ cancer information summary about breast cancer prevention states the risks succinctly: [include excerpt from the summary]."
The preferred citation for this PDQ summary is:
PDQ® Pediatric Treatment Editorial Board. PDQ Childhood Thyroid Cancer Treatment. Bethesda, MD: National Cancer Institute. Updated <MM/DD/YYYY>. Available at:
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Disclaimer
Based on the strength of the available evidence, treatment options may be described as either "standard" or "under clinical evaluation." These classifications should not be used as a basis for insurance reimbursement determinations. More information on insurance coverage is available on Cancer.gov on the
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