The annual incidence of thyroid cancers is 4.8 to 5.9 cases per 1 million people aged 0 to 19 years, accounting for approximately 1.5% of all cancers in this age group.[1,2] Thyroid cancer incidence is higher in children aged 15 to 19 years (17.6 cases per 1 million people), and it accounts for approximately 8% of all cancers arising in this older age group.[1,3] More thyroid carcinomas occur in females than in males.[4] The trend toward larger tumors suggests that diagnostic scrutiny is not the only explanation for the observed results.[5]
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.[1,5] A similar trend has been documented in Canada over the last two decades.[6] A Danish population-based study of thyroid cancer in patients younger than 24 years reported that the age-adjusted incidence rate (per 100,000) increased significantly, from 0.36 in 1980 to 0.97 in 2014, with an average annual change of 2.9%.[7] No change in overall survival was observed, but a significant increase was seen in the incidence of thyroid cancer among young adults (aged 18–24 years), mainly among females and patients with papillary carcinoma.
The incidence of thyroid cancer is higher in White people than in Black people (5.3 cases per 1 million vs. 1.5 cases per 1 million). It is also higher in female adolescents than in male adolescents (8.1 cases per 1 million vs. 1.7 cases per 1 million).[1]
The papillary subtype is the most common 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 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 highest in children aged 0 to 4 years and declines at older ages (see Figure 1).[2]
Risk factors for pediatric thyroid cancer include the following:
Papillary thyroid carcinoma is the most frequent form of thyroid carcinoma diagnosed after radiation exposure.[5] Molecular alterations, including intrachromosomal rearrangements, are frequently found; among them, RET rearrangements are the most common.[5]
Tumors of the thyroid are classified as adenomas or carcinomas.[1-3] Adenomas are benign, well circumscribed, and encapsulated nodules that may cause enlargement of all or part of the gland, which extends to both sides of the neck and can be quite large. Some tumors may secrete hormones. Transformation to a malignant carcinoma may occur in some cells, which may grow and spread to lymph nodes in the neck or to the lungs. Approximately 20% of thyroid nodules in children are malignant.[1,4]
The following histologies account for the general diagnostic category of carcinoma of the thyroid:
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.[1]
In a retrospective review, 131 pediatric patients with differentiated thyroid cancer were categorized into three groups: RAS-altered (HRAS, KRAS, or NRAS), BRAF-altered (BRAF p.V600E), and RET::NTRK fusion (RET, NTRK1, and NTRK3 fusions).[2] Patients with RET::NTRK fusions were significantly more likely to have advanced lymph node disease and distant metastasis and less likely to achieve remission at 1 year, compared with patients in the RAS-altered and BRAF-altered subgroups.
Variants in BRAF and RAS genes are the most common drivers, followed by gene fusions involving RET or NTRK:[3-5]
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).[3,5]
A retrospective analysis of 80 Brazilian patients younger than 18 years with papillary thyroid carcinoma identified AGK::BRAF fusions and BRAF V600E point variants.[6] AGK::BRAF fusions, found in 19% of pediatric patients with papillary thyroid carcinoma, were associated with distant metastasis and younger age. BRAF V600E variants, found in 15% of patients with pediatric papillary thyroid carcinoma, were correlated with older age and larger tumor size.
A retrospective review identified 113 RET fusion–positive tumors among 993 patients with papillary thyroid carcinoma.[8] RET fusion–positive tumors were three times more frequent in pediatric and adolescent patients (29.8%) than in adult patients (8.7%). A total of 20 types of RET fusions were identified. RET fusion–positive carcinomas were associated with aggressive tumor behavior, including high rates of lymph node metastases (75.2%) and distant metastases (18.6%). These rates were significantly higher than in carcinomas with NTRK fusions, BRAF V600E variants, and RAS variants. Local and distant metastases were also frequently found in patients with microcarcinomas positive for RET fusions. True recurrences occurred rarely (2.4%) and only in adult patients. The disease-specific survival rates were 99% at 2 years, 96% at 5 years, and 95% at 10 years.
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.[11] Fifteen papillary thyroid carcinomas (27%) harbored BRAF p.V600E. Eight cases of papillary thyroid carcinomas (14%) harbored DICER1 variants, with no associated BRAF p.V600E. DICER1 variants were identified in exons 26 and 27. A novel D1810del (c.5428_5430delGAT) variant was also detected. The study confirmed the absence of hotspot DICER1 variants in the matched nontumor tissue DNA in all eight DICER1-related papillary thyroid carcinomas. The study concluded that the increased incidence in female patients and enrichment in low-risk follicular-patterned papillary thyroid carcinomas are characteristics of DICER1-related papillary thyroid carcinomas.
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 2 were follicular thyroid cancers.[12]
Other alterations include the following:[3,5]
The spectrum of somatic genetic alterations seems to differ between pediatric and adult patients when analyzing tumors with similar histologies, as follows:[1,4,13,14]
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 oncogene associated with multiple endocrine neoplasia type 2 (MEN2), either MEN2A or MEN2B, depending on the specific variant. The highest medullary thyroid carcinoma risk is conferred by the RET M918T variant, which is associated with MEN2B. The RET variants associated with MEN2A confer a lower medullary thyroid carcinoma risk.[4]
Patients with thyroid cancer usually present with a thyroid mass with or without painless cervical adenopathy.[1] On the basis of medical and family history and clinical constellation, the thyroid cancer may be part of a tumor predisposition syndrome such as multiple endocrine neoplasia (MEN), APC-associated polyposis, PTEN hamartoma tumor syndrome, Carney complex, Werner syndrome, or DICER1 syndrome.[2,3]
Younger age is associated with a more aggressive clinical presentation in differentiated thyroid carcinoma. The following observations have been reported:
In well-differentiated thyroid cancer, male sex, large 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.[11] A French registry analysis found similar outcomes in children and young adults who developed papillary thyroid carcinoma after previous radiation therapy compared with children and young adults who developed spontaneous papillary thyroid carcinoma. However, patients with previous thyroid irradiation for benign disease presented with more invasive tumors and lymph node involvement.[12]
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.[13]
Children with medullary thyroid carcinoma present with a more aggressive clinical course; 50% of the cases have hematogenous metastases at diagnosis.[14] The National Cancer Institute is conducting a natural history study of children and young adults with medullary thyroid cancer (NCT01660984). A review of 430 patients aged 0 to 21 years with medullary thyroid cancer reported that older age (16–21 years) at diagnosis, tumor diameter greater than 2 cm, positive margins after total thyroidectomy, and lymph node metastases were associated with a worse prognosis.[15]
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.[16][Level of evidence C1] In patients with medullary thyroid carcinoma, the median follow-up was 5 years (range, 0–19 years), and the median age at diagnosis was 10 years (range, 0–17 years). The overall survival rate was 87%, and the event-free survival (EFS) rate was 52%. In total, 96.4% of patients were affected by MEN type 2 (MEN2) syndromes; 37 of 42 patients had MEN2A, and 3 of 28 patients had MEN2B (RET M918T variant). The 10-year EFS rate was 78% for patients with MEN2A and 38% for patients with MEN2B (P < .001). In multivariate analyses, positive lymph node status and postoperatively elevated calcitonin levels were significant adverse prognostic factors for EFS.
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, with a varying degree of risk of developing pheochromocytoma and hyperparathyroidism in MEN2A based on the specific RET variant.[17,18] For more information, see Childhood Multiple Endocrine Neoplasia (MEN) Syndromes Treatment.
Initial evaluation of a child or adolescent with a thyroid nodule includes the following:
Tests of thyroid function are usually normal, but thyroglobulin can be elevated.
Fine-needle aspiration as an initial diagnostic approach is sensitive and useful. However, in doubtful cases, open biopsy or resection should be considered.[1]
Cancer in children and adolescents is rare, although the overall incidence has been slowly increasing since 1975.[1] Referral to medical centers with multidisciplinary teams of cancer specialists experienced in treating cancers that occur in childhood and adolescence should be considered. This multidisciplinary team approach incorporates the skills of the following health care professionals and others to ensure that children receive treatment, supportive care, and rehabilitation that will achieve optimal survival and quality of life:
For information about supportive care for children and adolescents with cancer, see the summaries on Supportive and Palliative Care.
The American Academy of Pediatrics has outlined guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer.[2] At these pediatric cancer centers, clinical trials are available for most types of cancer that occur in children and adolescents, and the opportunity to participate is offered to most patients and their families. Clinical trials for children and adolescents diagnosed with cancer are generally designed to compare potentially better therapy with current standard therapy. Most of the progress made in identifying curative therapy for childhood cancers has been achieved through clinical trials. Information about ongoing clinical trials is available from the NCI website.
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%.[3-5] Childhood and adolescent cancer survivors require close monitoring because side effects of cancer therapy may persist or develop months or years after treatment. For more information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors, see Late Effects of Treatment for Childhood Cancer.
Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years.[6] The U.S. Rare Diseases Act of 2002 defines a rare disease as one that affects populations smaller than 200,000 people. Therefore, all pediatric cancers are considered rare.
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.[7,8] Also, the designation of a pediatric rare tumor is not uniform among international groups, as follows:
Most cancers in subgroup XI are either melanomas or thyroid cancers, with other cancer types accounting for only 2% of the cancers in children aged 0 to 14 years and 9.3% of the cancers in adolescents aged 15 to 19 years.
These rare cancers are extremely challenging to study because of the low number of patients with any individual diagnosis, the predominance of rare cancers in the adolescent population, and the lack 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 the PDQ summary on Thyroid Cancer Treatment.
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. These guidelines (summarized below) are based on scientific evidence and expert panel opinion, with a careful assessment of the level of evidence.[1]
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.
For patients with papillary or follicular carcinoma, total thyroidectomy is the recommended treatment of choice. 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—whereby 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.[2]
A retrospective analysis identified factors associated with bilateral thyroid involvement in 115 pediatric patients with well-differentiated thyroid cancer.[3] Bilateral disease was present in 47 of 115 participants (41%). In multivariable analysis, only multifocality in the primary lobe was independently associated with bilateral disease (odds ratio, 7.61; 95% confidence interval, 2.44–23.8; P < .001). Among clinically node-negative patients with papillary carcinoma who did not have tumor multifocality in the primary lobe, bilateral disease was present in 5 of 32 patients (16%). The authors concluded that in children with differentiated thyroid cancer, tumor multifocality in the primary lobe is associated with bilateral disease, and they recommended prompt consideration of complete thyroidectomy after initial lobectomy.
Another multicenter retrospective analysis evaluated the prevalence of and risk factors for multifocal disease in 212 pediatric patients with papillary thyroid carcinoma.[4] The mean age at diagnosis was 14.1 years, and 23 patients were aged 10 years or younger. A total of 173 patients (82%) were female. Any amount of multifocal disease was present in 98 cases (46%), with bilateral multifocal disease present in 73 cases (34%). Predictors of multifocal and bilateral multifocal disease included age 10 years or younger, T3 tumor stage, and N1b nodal stage. The authors concluded that these risk factors and the high prevalence of multifocal disease should be considered when assessing the risks and benefits of surgical management options in pediatric patients with papillary thyroid carcinoma.
Total thyroidectomy also optimizes the use of radioactive iodine for imaging and treatment.
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. This categorization strategy is meant to define the risk of persistent cervical disease and help determine which patients should undergo postoperative staging for the presence of distant metastasis.
For more information about the TNM system, see the Stage Information for Thyroid Cancer section in Thyroid Cancer Treatment.
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 iodine I 131 (131I). The ATA Pediatric Risk Level (as defined above) helps determine the extent of postoperative testing.
For patients with antithyroglobulin antibodies, consideration can be given to deferred postoperative staging to allow time for antibody clearance, except in patients with T4 or M1 disease.
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.[7]
Despite having more advanced disease at presentation than adults, children with differentiated thyroid cancer generally have an excellent survival with relatively few side effects.[1-3]
Treatment options for recurrent papillary and follicular thyroid carcinoma include the following:
Radioactive iodine ablation with 131I is usually effective after recurrence.[4] For patients with 131I-refractory disease, molecularly targeted therapies using kinase inhibitors may provide alternative therapies.
Tyrosine kinase inhibitors (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.[6]
Three children with papillary thyroid carcinoma who were refractory to radioactive iodine had a clinical response to lenvatinib.[8]
For more information, see Thyroid Cancer Treatment.
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
Medullary thyroid carcinomas are commonly associated with the multiple endocrine neoplasia type 2 (MEN2) syndrome. For more information, see Childhood Multiple Endocrine Neoplasia (MEN) Syndromes Treatment.
Treatment options for medullary thyroid carcinoma include the following:
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 variant. Strong genotype-phenotype correlations have facilitated the development of guidelines for intervention, including screening and age at which prophylactic thyroidectomy should occur.[2]
A retrospective analysis identified 167 children with RET variants who underwent prophylactic thyroidectomy. This group included 109 patients without a concomitant central node dissection and 58 patients with a concomitant central node dissection. Postoperative hypoparathyroidism was more frequent in older children (32% in the oldest age group vs. 3% in the youngest age group; P = .002), regardless of whether central node dissection was carried out. Three children developed recurrent laryngeal nerve palsy, all of whom had undergone central node dissection (P = .040). All complications resolved within 6 months. Postoperative normalization of calcitonin serum levels was achieved in 114 of 115 children (99.1%) with raised preoperative values. Children were classified into risk groups by their specific type of RET variant (see Table 1).[3]
The American Thyroid Association has proposed the following guidelines for prophylactic thyroidectomy in children with hereditary medullary thyroid carcinoma (see Table 1).[2]
Medullary Thyroid Carcinoma Risk Level | |||
---|---|---|---|
Highest (MEN2B) | High (MEN2A) | Moderate (MEN2A) | |
MEN2A = multiple endocrine neoplasia type 2A; MEN2B = multiple endocrine neoplasia type 2B. | |||
aAdapted from Wells et al.[2] | |||
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 levels. | 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. |
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 a partial response, 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.[6] A long-term outcome evaluation in a cohort of 17 children and adolescents with advanced medullary thyroid carcinoma who received vandetanib reported a median PFS of 6.7 years and a 5-year overall survival of 88.2%.[7]
For more information, see Childhood Multiple Endocrine Neoplasia (MEN) Syndromes Treatment and the Treatment for Medullary Thyroid Cancer (MTC) section in Genetics of Endocrine and Neuroendocrine Neoplasias.
Information about National Cancer Institute (NCI)–supported clinical trials can be found on the NCI website. For information about clinical trials sponsored by other organizations, see the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
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.
Added text about the results of a retrospective review that identified 113 RET fusion–positive tumors among 993 patients with papillary thyroid carcinoma (cited Bulanova et al. as reference 8).
Added text to state that 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 2 were follicular thyroid cancers (cited Ricarte-Filho et al. as reference 12).
This summary is written and maintained by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of NCI. The summary reflects an independent review of the literature and does not represent a policy statement of NCI or NIH. More information about summary policies and the role of the PDQ Editorial Boards in maintaining the PDQ summaries can be found on the About This PDQ Summary and PDQ® Cancer Information for Health Professionals pages.
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.
This summary is reviewed regularly and updated as necessary by the PDQ Pediatric Treatment Editorial Board, which is editorially independent of the National Cancer Institute (NCI). The summary reflects an independent review of the literature and does not represent a policy statement of NCI or the National Institutes of Health (NIH).
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 Email Us. Do not contact the individual Board Members with questions or comments about the summaries. Board members will not respond to individual inquiries.
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 formal evidence ranking system in developing its level-of-evidence designations.
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: https://www.cancer.gov/types/thyroid/hp/child-thyroid-treatment-pdq. Accessed <MM/DD/YYYY>. [PMID: 26389315]
Images in this summary are used with permission of the author(s), artist, and/or publisher for use within the PDQ summaries only. Permission to use images outside the context of PDQ information must be obtained from the owner(s) and cannot be granted by the National Cancer Institute. Information about using the illustrations in this summary, along with many other cancer-related images, is available in Visuals Online, a collection of over 2,000 scientific images.
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 Managing Cancer Care page.
More information about contacting us or receiving help with the Cancer.gov website can be found on our Contact Us for Help page. Questions can also be submitted to Cancer.gov through the website’s Email Us.