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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 cancers arising in this older age group.[1,3] More thyroid carcinomas occur in females than in males. The trend toward larger tumors suggests that diagnostic scrutiny is not the only explanation for the observed results.
Two time-trend studies using the Surveillance, Epidemiology, and End Results (SEER) 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 towards an increase in the incidence of thyroid cancer among children, adolescents, and young adults over the last two decades has been documented in Canada. 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 percent change of 2.9%. 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 attributed to an increase among females and patients with papillary carcinoma.
The incidence of thyroid cancer is higher in whites (5.3 cases per 1 million vs. 1.5 cases per 1 million in blacks) and female adolescents (8.1 cases per 1 million vs. 1.7 cases per 1 million in male adolescents).
The papillary subtype is the most common, accounting for approximately 60% of the 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 the highest in the age group of 0 to 4 years and declines at older ages (refer to Figure 1).
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.
Risk factors for pediatric thyroid cancer include the following:
Papillary thyroid carcinoma is the most frequent form of thyroid carcinoma diagnosed after radiation exposure. Molecular alterations, including intrachromosomal rearrangements, are frequently found; among them, RET/PTC rearrangements are the most common.
Tumors of the thyroid are classified as adenomas or carcinomas.[1,2,3] 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 Carcinoma of Follicular Cells
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. Mutations in BRAF and RAS genes are the most common driver events, followed by gene fusions involving RET or NTRK:[1,2,3]
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).[1,3]
A retrospective analysis of 80 Brazilian patients younger than 18 years with papillary thyroid carcinoma identified AGK-BRAF fusions and BRAF V600E point mutations.AGK-BRAF fusions, found in 19% of pediatric patients with papillary thyroid carcinoma, were associated with distant metastasis and younger age. BRAF V600E mutations, found in 15% of patients with pediatric papillary thyroid carcinoma, were correlated with older age and larger tumor size.
Other alterations include the following:[1,3]
The spectrum of somatic genetic alterations seems to be different between pediatric and adult patients when analyzing tumors with similar histologies, as follows:
Medullary Thyroid Carcinoma
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 mutation in the RET oncogene associated with multiple endocrine neoplasia type 2 (MEN2), either MEN2A or MEN2B, depending on the specific mutation. The highest medullary thyroid carcinoma risk is conferred by the RET M918T mutation, which is associated with MEN2B; the RET mutations associated with MEN2A confer a lower medullary thyroid carcinoma risk.
Differentiated Thyroid Carcinoma
Patients with thyroid cancer usually present with a thyroid mass with or without painless cervical adenopathy. 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, and 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. 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; patients with previous thyroid irradiation for benign disease, however, presented with more invasive tumors and lymph node involvement.
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.
Children with medullary thyroid carcinoma present with a more aggressive clinical course; 50% of the cases have hematogenous metastases at diagnosis. A natural history study of children and young adults with medullary thyroid cancer is being conducted by the National Cancer Institute (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.
From 1997 to 2019, the German Society for Pediatric Oncology and Hematology (GPOH)–Malignant Endocrine Tumors (MET) registry identified a total of 57 patients with medullary thyroid carcinoma and 17 patients with C-cell hyperplasia.[Level of evidence: 3iA] 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 mutation). 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 recognition and diagnosis because the RET M918T mutation 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 mutation.[13,14] (Refer to the PDQ summary on Childhood Multiple Endocrine Neoplasia [MEN] Syndromes Treatment for more information.)
For children with de novo RET mutations and no familial history, nonendocrine manifestations, such as intestinal ganglioneuromatosis or skeletal or ocular stigmata, may facilitate early diagnosis and result in better outcomes.
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.
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.
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.
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. (Refer to the Stage Information for Thyroid Cancer section in the PDQ summary on Thyroid Cancer Treatment [Adult] for more information about the TNM system.) 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.
Initial staging should be performed within 12 weeks after surgery; the purpose is 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 the risks of recurrence and to decrease 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.
Larotrectinib (a targeted therapy) has been used to treat patients with TRK fusion–positive thyroid carcinoma. Five of five patients with TRK fusion–positive thyroid carcinomas who were treated with larotrectinib therapy achieved partial or complete responses.
Despite the more advanced disease at presentation compared with adults, children with differentiated thyroid cancer generally have an excellent survival with relatively few side effects.[1,2,3]
Treatment options for recurrent papillary and follicular thyroid carcinoma include the following:
Radioactive iodine ablation with 131I is usually effective after recurrence. 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 very 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.
(Refer to the PDQ summary on Thyroid Cancer Treatment [Adult] for more information.)
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 NCI website. For information about clinical trials sponsored by other organizations, refer to the ClinicalTrials.gov website.
The following is an example of a national and/or institutional clinical trial that is currently being conducted:
Tumor tissue from progressive or recurrent disease must be available for molecular characterization. Patients with tumors that have molecular variants addressed by treatment arms included in the trial will be offered treatment on Pediatric MATCH. Additional information can be obtained on the NCI website and ClinicalTrials.gov website.
Medullary thyroid carcinomas are commonly associated with the multiple endocrine neoplasia type 2 (MEN2) syndrome (refer to the PDQ summary on Childhood Multiple Endocrine Neoplasia [MEN] Syndromes Treatment for more information).
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 mutation. Strong genotype-phenotype correlations have facilitated the development of guidelines for intervention, including screening and age at which prophylactic thyroidectomy should occur.
A retrospective analysis identified 167 children with RET mutations 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 mutation (refer to Table 1).
The American Thyroid Association has proposed the following guidelines for prophylactic thyroidectomy in children with hereditary medullary thyroid carcinoma (refer to Table 1).
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. 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%.
(Refer to the PDQ summary on Childhood Multiple Endocrine Neoplasia [MEN] Syndromes Treatment and the Treatment for Medullary Thyroid Cancer [MTC] section in the PDQ summary on Genetics of Endocrine and Neuroendocrine Neoplasias for more information.)
Treatment Options Under Clinical Evaluation for Medullary Thyroid Carcinoma
Cancer in children and adolescents is rare, although the overall incidence of childhood cancer has been slowly increasing since 1975. Referral to medical centers with multidisciplinary teams of cancer specialists experienced in treating cancers that occur in childhood and adolescence should be considered for children and adolescents with cancer. 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:
(Refer to the PDQ Supportive and Palliative Care summaries for specific information about supportive care for children and adolescents with cancer.)
Guidelines for pediatric cancer centers and their role in the treatment of pediatric patients with cancer have been outlined by the American Academy of Pediatrics. 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 in these trials 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 therapy that is currently accepted as standard. 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 2010, childhood cancer mortality decreased by more than 50%. Childhood and adolescent cancer survivors require close monitoring because cancer therapy side effects may persist or develop months or years after treatment. (Refer to the PDQ summary on Late Effects of Treatment for Childhood Cancer for specific information about the incidence, type, and monitoring of late effects in childhood and adolescent cancer survivors.)
Childhood cancer is a rare disease, with about 15,000 cases diagnosed annually in the United States in individuals younger than 20 years. The U.S. Rare Diseases Act of 2002 defines a rare disease as one that affects populations smaller than 200,000 persons. Therefore, all pediatric cancers are considered rare.
The designation of a rare tumor is not uniform among pediatric and adult groups. Adult rare cancers are defined as those with an annual incidence of fewer than six cases per 100,000 people, and they are estimated to account for up to 24% of all cancers diagnosed in the European Union and about 20% of all cancers diagnosed in the United States.[5,6] Also, the designation of a pediatric rare tumor is not uniform among international groups, as follows:
Most cancers within subgroup XI are either melanomas or thyroid cancer, with the remaining subgroup XI cancer types accounting for only 1.3% of cancers in children aged 0 to 14 years and 5.3% of cancers in adolescents aged 15 to 19 years.
These rare cancers are extremely challenging to study because of the low incidence 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 (Adult).
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.
Clinical Presentation and Prognostic Factors
Added text about the results of a German Society for Pediatric Oncology and Hematology–Malignant Endocrine Tumors registry study that identified a total of 57 patients with medullary thyroid carcinoma and 17 patients with C-cell hyperplasia (cited Kuhlen et al. as reference 12 and level of evidence 3iA).
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® - NCI's Comprehensive Cancer Database pages.
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 who care for cancer 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 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.
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 formal evidence ranking system in developing its level-of-evidence designations.
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: 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.
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Last Revised: 2020-06-08
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