Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer

Publication Date: July 10, 2015
Last Updated: September 2, 2022

Key Points

The pediatric age should be limited to a patient ≤18 years of age. Establishing a uniform upper limit of age will afford an opportunity to better define the potential impact of growth on tumor behavior. From a pragmatic point of view, individual centers may transition pediatric patients to adult care anywhere between 18 and 21 years of age. Clinicians may manage the "child" under these guidelines until transition has been completed. ( C )
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Thyroid Nodules

Diagnosis

The evaluation and treatment of thyroid nodules in children (Figure 1) should be the same as in adults with the exceptions that:
  • US characteristics and clinical context should be used rather than size alone to identify nodules that warrant FNA.
  • All FNA in children should be performed under US-guidance.
  • Preoperative FNA of a hyperfunctioning nodule in a child is not warranted as long as the lesion is removed.
  • A diffusely infiltrative form of PTC may occur in children and should be considered in a clinically suspicious gland.
  • Surgery (lobectomy + isthmusectomy) is favored over repeat FNA for most nodules with indeterminate cytology.
( B )
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A positive mutational test appears highly likely to be associated with malignancy. Conversely, insufficient data exist in children to rely on negative genetic studies to reliably exclude malignancy. Although molecular studies hold promise for complementing the results of FNA, particularly for nodules that yield indeterminate cytology, they have not yet been sufficiently validated in children and cannot be routinely recommended in routine clinical practice until further studies are conducted. ( E )
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For patients with autoimmune thyroiditis, evaluation by an experienced thyroid ultrasonographer should be pursued in any patient with a suspicious thyroid examination (suspected nodule or significant gland asymmetry), especially if associated with palpable cervical lymphadenopathy. ( B )
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Treatment of Benign Nodules

We are unable to recommend for or against the routine use of LT4 therapy for children with benign thyroid nodules. In general, the data support the efficacy of LT4 therapy to reduce the size and risk of subsequent nodule formation but there are no data to weigh this potential benefit against the potential risks of long-term suppression therapy. In patients with compressive symptoms or a history of radiation exposure the benefits of LT4 therapy may be more apparent. ( I )
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Benign lesions should be followed by serial US (see Figure 1) and undergo repeat FNA if suspicious features develop or the lesion continues to grow. Lobectomy may be performed in patients with compressive symptoms, cosmetic concerns, or patient/parent preference and should be considered in all apparently benign solid thyroid nodules >4cm, those lesions demonstrating significant growth, or in the presence of other clinical concerns for malignancy. ( B )
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For pediatric patients with a suppressed TSH associated with a thyroid nodule, thyroid scintigraphy should be pursued. Increased uptake within the nodule is consistent with autonomous nodular function. Surgical resection, most commonly lobectomy, is the recommended approach for most autonomous nodules in children and adolescents. ( A )
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Differentiated Thyroid Cancer

Diagnosis

An annual physical exam is recommended in children at high risk for thyroid neoplasia. Additional imaging should be pursued if palpable nodules, thyroid asymmetry and/or abnormal cervical lymphadenopathy are found on exam. ( B )
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In children with a history of radiation exposure to the thyroid, the data show that US can detect small thyroid nodules, but the panel is not yet convinced that detection of subclinical disease by US prior to a palpable abnormality on physical exam impacts long-term outcomes. Therefore, routine screening US in high-risk children can neither be recommended for nor against until more data become available. ( I )
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Patients at increased risk of developing familial DTC should be referred to centers of excellence so that appropriate evaluation, follow-up, genetic counseling and/or treatment can be undertaken without subjecting patients and families to unwarranted and aggressive therapy. (C)
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The AJCC TNM Classification System should be used to describe the extent of disease in pediatric patients with PTC (Table 2). Children with PTC should be stratified into risk levels (ATA Pediatric Low-, Intermediate-, or High-Risk) based on clinical presentation, tumor size and evidence of regional invasion and metastasis (Table 3). The extent of disease in the neck at diagnosis appears to correlate best with the risk for distant metastasis and/or persistent disease that may require additional treatment. ( B )
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Patients found to have disease confined to the thyroid gland, as well as incidental evidence of minimal, microscopic disease to lymph nodes in the central neck (level VI), fall into the ATA Pediatric Low-Risk level (Table 3). The presence of extensive, extra-thyroidal invasion or metastasis defines patients at greater risk for persistent regional or distant metastasis. Patients with these features are categorized within the ATA Pediatric Intermediate- or High-Risk levels (Table 3). Within these categories, additional postoperative staging is warranted to better define which patients may or may not benefit from additional therapy. ( B )
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It remains unclear if younger children (<10-15 years of age) are at greater risk for more extensive disease or higher rates of recurrence. Other factors aside from age (treatment approaches, genetic susceptibility, and/or radiation exposure) may interact to modify this risk. However, those studies with a larger proportion of young children show an increased risk of persistent disease/recurrence. In an effort to increase the descriptive nature of these discussions, the committee recommends that "prepubertal" and "pubertal/postpubertal" should be incorporated into future studies to increase uniformity and more accurately represent the potential influence of pubertal development on the incidence and behavior of DTC within the pediatric population. ( B )
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Treatment

Children with DTC should be cared for by teams of physicians experienced in the management of DTC in children. This will facilitate interdisciplinary decisions regarding optimal therapy and will help to reduce the possibility that treatment and long-term follow up will be either overly aggressive or inadequate. ( C )
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Surgery

Pediatric thyroid surgery, especially if compartment-focused lymph node resection is indicated, should ideally be performed by a surgeon who performs at least 30 or more cervical endocrine procedures annually. Thyroid surgery performed under these guidelines is associated with lower complications rates, decreased hospital stay and lower cost. ( B )
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A comprehensive neck US to interrogate all regions of the neck is required in order to optimize the pre-operative surgical plan. FNA of suspicious lateral neck lymph nodes is recommended. Anatomic imaging by MRI or CT with contrast should be considered in patients with large or fixed thyroid masses, vocal cord paralysis, or bulky metastatic lymphadenopathy in order to optimize surgical planning. ( A )
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For the majority of children, total thyroidectomy is recommended. The rationale for this approach is based on multiple studies showing an increased incidence of bilateral and multi-focal disease. In long-term analysis, bilateral lobar resection compared with lobectomy has been shown to decrease the risk for persistent/recurrent disease. ( A )
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CND is recommended for children with malignant cytology and clinical evidence of gross extrathyroidal invasion and/or loco-regional metastasis on pre-operative staging or intra-operative findings. This approach may be associated with a decreased need for second surgical procedures and increased DFS. ( B )
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For patients with PTC and no clinical evidence of gross extrathyroidal invasion and/or loco-regional metastasis, prophylactic CND may be selectively considered based upon tumor focality and size and the experience of the surgeon. For patients with unifocal disease, ipsilateral CND, with pursuit of contralateral CND based on intra-operative findings, may help balance the risks and benefits. ( C )
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Compartment-oriented resection is the recommended approach for lymph node dissection. "Berry picking" and attempting to use palpation to determine if metastatic disease is present in a lymph node are not recommended. ( A )
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Future studies to assess if TT with prophylactic CND dissection will lead to reduced reliance on 131I treatment, re-operative procedures, and improved DFS are recommended. ( C )
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Cytological confirmation of metastatic disease to lymph nodes in the lateral neck is recommended prior to surgery. Routine prophylactic lateral neck dissection (levels III, IV, anterior V, and II) is not recommended. However, lateral neck dissection should be performed on patients with cytologic evidence of metastases to the lateral neck. Measurement of Tg in the FNA washout can be considered if the cytological diagnosis is equivocal. ( B )
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The early incorporation of calcium and calcitriol in patients at high-risk for hypocalcemia may decrease the risks of symptomatic hypocalcemia. Postoperative iPTH measurement may be used to help predict which patients would benefit from more intensive monitoring and treatment. ( B )
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Postoperative staging is usually performed within 12 weeks after surgery (Figure 2) and allows for stratification of patients who may or may not benefit from further therapy, to include additional surgery or 131I therapy. ATA Pediatric Low- Risk patients may be initially assessed and followed with a TSH-suppressed Tg alone. In contrast, a TSH-stimulated Tg and a DxWBS is typically recommended to assess for evidence of persistent disease in ATA Pediatric Intermediate- and High-Risk patients. Additional imaging, to include neck US and/or hybrid imaging using SPECT/CT, may be used conjunctively to more accurately define the anatomic location of RAI uptake noted on a DxWBS. Whenever possible, 123I should be used for the DxWBS. ( B )
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131I Treatment

131I is indicated for treatment of iodine-avid persistent locoregional or nodal disease that cannot be resected as well as known or presumed iodine-avid distant metastases. For patients with persistent disease following 131I administration, the decision to pursue additional 131I therapy should be individualized according to clinical data and previous response (Figures 3 and 4). The potential risks and benefits must be weighed on an individual basis. ( B )
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In order to facilitate 131I uptake by residual iodine-avid cancer, the TSH should be above 30 mIU/L. This can be achieved in almost all children by withdrawing LT4 for ≥14 days. In selected patients who cannot mount an adequate TSH response or cannot tolerate profound hypothyroidism, rhTSH may be considered. Low iodine diets have not been specifically evaluated in children but may enhance the effective radiation activity of 131I and are recommended. ( A )
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Adequate hydration should be ensured in all children receiving therapeutic 131I to facilitate clearance of the radioisotope, and additional supportive care with antiemetic medications and stool softeners/laxatives should be considered. Sour candy or lemon drops can be given after 131I treatment, but not all experts ascribe to this practice. ( C )
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The routine use of lithium and amifostine cannot be recommended. ( F )
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Based on the lack of data comparing empiric treatment and treatment informed by dosimetry, we are unable to recommend for or against either approach in most patients. Many experts provide the first activity of 131I based on an empiric estimate and reserve dosimetry for patients with diffuse pulmonary metastases or subsequent activities of 131I in patients with iodine-avid distant metastases who require additional therapy. However, dosimetry can be considered prior to the first 131I treatment in small children and in patients with limited bone marrow reserve. Due to the differences in body size and iodine clearance in children compared with adults, it is recommended that all activities of 131I should be calculated by experts with experience in dosing children. ( I )
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A posttreatment WBS is recommended for all children 4-7 days after 131I therapy. The addition of SPECT-CT may help to distinguish the anatomic location of focal uptake. ( B )
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There are clear benefits and risks, both acute and chronic, following administration of 131I during childhood. The challenge is to define those patients for whom the benefits of 131I therapy outweigh the risks. Families should be provided full disclosure of the risks and benefits of 131I and their opinion must be considered in the final decision. ( C )
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Surveillance And Follow Up

Children with DTC may experience adverse psychosocial effects and be nonadherent with LT4 therapy. Attention to these possibilities and supportive counseling as required are important adjuncts in the long-term follow up of children with DTC. Future studies on the impact of a DTC diagnosis and treatment on quality of life in children are required. ( C )
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Recurrence of DTC in children has been reported as long as 40 years after initial therapy. For that reason, children with DTC should be followed for life, albeit with decreasing intensity for those with no evidence for disease. ( B )
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Tg serves as a sensitive tumor marker in the evaluation, treatment, and long-term follow up of DTC in children, even in children not previously treated with 131I. TgAb levels should be simultaneously measured in all samples since the presence of TgAb will render the Tg result uninterpretable. Tg and TgAb levels should be measured using the same laboratory and assay technique. The trend in serial Tg and/or TgAb levels is much more informative in regard to determining disease status than any single measurement. ( A )
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An undetectable TSH-stimulated Tg (with negative TgAb) identifies patients in remission with a very high probability to remain completely free of disease during follow-up and in whom the intensity of disease surveillance and the magnitude of TSH suppression should be relaxed. Monitoring the TSH-suppressed Tg level on LT4 treatment is the recommended approach to long-term follow-up, with the trend of this value being the most reliable indicator of disease activity. Repeat TSH-stimulated Tg levels are not necessary if the TSH-suppressed Tg is detectable or if a previous TSH-stimulated Tg was undetectable. ( A )
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Detection of a low-level TSH-stimulated Tg<10 ng/ml) in a patient who has undergone surgery and therapeutic 131I may indicate persistent disease. However, this value may decline over time without additional therapy. Continued follow up with serial TSH-suppressed Tg and TgAb levels as well as radiologic imaging (neck US) are indicated in this situation. ( B )
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Increasing or frankly elevated levels of TSH-stimulated Tg (>10 ng/ml) warrant further evaluation to localize disease and inform the decision as to whether additional surgery and/or 131I therapy would be beneficial or whether one should pursue continued observation. ( A )
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The Tg level cannot be interpreted in children with positive TgAb. In this setting, the TgAb trend should be followed using the same assay. If the TgAb trend is clearly rising, then further evaluation is warranted. ( A )
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Neck US is recommended in the follow-up of children with PTC (Table 3 and Figure 3). Neck US should be performed at least 6 months after initial surgery and then at 6-12 month intervals for ATA Pediatric Intermediate- and High-Risk patients and at annual intervals for ATA Pediatric Low-Risk patients. Follow-up beyond 5 years should be individualized based on recurrence risk. ( A )
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During the follow up of children with PTC who are suspected to have residual disease, a DxWBS can be used to inform the decision of whether or not to use 131I and the activity of 131I to be administered (Figure 3). A final DxWBS can be considered to confirm the absence of iodine-avid disease in children who were previously treated with 131I and who have no evidence of disease 1-2 years after initial therapy. ( C )
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A DxWBS should be performed in children with ATA Pediatric High-Risk disease who were previously treated with 131I or known to have iodine-avid metastatic disease based upon a previous posttreatment scan. The DxWBS should be obtained after at least 12 months of clinical follow-up, and deferred even longer in those children who continue to demonstrate a clinical response to previous treatment. ( C )
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Once a negative DxWBS is obtained, there is no benefit from serial DxWBS to survey for disease recurrence as long as the patient otherwise remains without clinical evidence of disease. ( B )
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For the child with a detectable TSH-suppressed Tg but a negative cervical US and DxWBS, contrast-enhanced cross-sectional imaging of the neck and chest should be considered once iodine excess has been eliminated as a cause of a false negative DxWBS. (B)
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The utility of 18FDG-PET/CT is poorly studied in pediatric DTC, and 18FDG-PET/CT cannot be routinely recommended in the care of children who have persistent evidence of DTC on follow-up. ( D )
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Empiric 131I therapy and a posttreatment scan are not recommended to localize disease in the child with DTC and a negative DxWBS unless there is evidence for clinical progression (e.g. a rising Tg level) and a documented clinical response to previous 131I therapy. ( D )
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TSH Suppression Therapy

TSH suppression in children with DTC should be determined by ATA Pediatric Risk level and current disease status (Table 3). In children with known or suspected persistent disease, TSH suppression should be maintained. In children with no evidence of disease, the TSH can be normalized to the low/normal range after an appropriate period of surveillance. ( B )
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Persistent/Recurrent Cervical Disease

The decision to treat or to observe structurally identifiable cervical disease should be individualized and include considerations of age, initial ATA Pediatric Risk classification, the presence of distant metastases, and prior treatment history (including complications from previous therapy), in addition to the size, extent, anatomic location and iodine avidity of the disease (see Figure 3). ( C )
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Children with macroscopic cervical disease (>1 cm in size) should be assessed by a high-volume thyroid surgeon to determine the feasibility of additional surgery. ( B )
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Iodine-avid cervical disease (visualized with DxWBS) could be treated with surgery or 131I depending on individual patient risks and the presence or absence of distant metastases. Surgery would be favored for disease localized to the neck, especially if located in a lymph node compartment not previously operated upon. ( B )
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If repeat surgery is performed, postoperative re-staging can be utilized to determine whether additional 131I treatment is warranted, especially in the patient who has not received previous therapeutic 131I. ( B )
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Pulmonary Metastases

Children with RAI-avid pulmonary metastases visualized with a DxWBS are good candidates for 131I therapy. ( B )
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After a therapeutic activity of 131I, the TSH-suppressed Tg level and imaging studies should be monitored until the full clinical and biochemical (Tg) response is reached. ( B )
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If the full clinical and biochemical (Tg) response suggests persistent disease or if there is documented disease progression >12 months after 131I therapy, further evaluation with a DxWBS and a TSH-stimulated Tg is indicated. ( B )
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Re-treatment of RAI-avid pulmonary metastases should be considered in children who have demonstrated progression of disease and a previous response to 131I, with each treatment carefully individualized based on the child’s unique clinical course, side-effect profile, risk tolerance, and cumulative administered 131I activity. Treatment with 131I should be performed by experts with experience in managing children with pulmonary metastases. ( B )
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Re-treatment of pulmonary metastases with 131I is not recommended in children who do not have uptake on a DxWBS and who have not demonstrated a previous response to 131I. ( E )
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Pulmonary function testing should be considered in all children with diffuse pulmonary metastases, especially if multiple 131I treatments are planned. ( C )
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Children with incidental PTC should be managed similarly to other children with ATA Pediatric Low-Risk disease. Neck US is recommended to detect contralateral disease or disease in the regional lymph nodes. Completion thyroidectomy is not required in those children who had less than a TT unless there is US evidence and cytologic confirmation of contralateral thyroid disease or malignant lymphadenopathy. ( B )
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Most children with asymptomatic and non-progressive 131I-refractory disease can be safely monitored while continuing TSH suppression. Systemic treatment for advanced thyroid cancer in children remains unstudied and at this time should be considered the purview of specialized centers for the treatment of children with thyroid cancer. Consultation with experts in this area should be invited prior to initiation of treatment. In exceptional cases where systemic treatment is contemplated, clinical trials are preferred. If unavailable, the use of oral kinase inhibitors may be considered. ( C )
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Follicular Thyroid Carcinoma

Pediatric FTC is a rare malignancy. Because of the paucity of data regarding FTC in children, strong recommendations regarding therapy cannot be made and further studies are required to better understand the long-term outcomes and to risk-stratify children who would benefit from more extensive thyroid surgery and 131I therapy.
Patients with clear evidence of vascular invasion (>3 involved blood vessels), known distant metastasis, and/or tumor size >4 cm should be treated with total thyroidectomy and staged postoperatively with RAI. ( C )
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Minimally-invasive FTC <4 cm in size and with no or minimal vascular invasion (≤3 involved blood vessels) should be treated on a case-by-case basis but lobectomy alone rather than total thyroidectomy with 131I therapy may be sufficient ( C )
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In all children diagnosed with FTC, consideration should be given to genetic counseling and genetic testing for germline PTEN mutations particularly in the child with macrocephaly or with a family history suggestive of the PTEN hamartoma tumor syndrome. ( C )
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Recommendation Grading

Overview

Title

Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer

Authoring Organization

Endorsing Organization

Publication Month/Year

July 10, 2015

Last Updated Month/Year

April 2, 2024

Document Type

Guideline

External Publication Status

Published

Country of Publication

US

Inclusion Criteria

Male, Female, Adolescent, Child

Health Care Settings

Ambulatory, Hospital, Outpatient

Intended Users

Nurse, nurse practitioner, physician, physician assistant

Scope

Diagnosis, Assessment and screening, Treatment, Management, Prevention

Keywords

children, differentiated thyroid cancer (DTC), thyroid nodules, DTC

Methodology

Number of Source Documents
405
Literature Search Start Date
December 31, 2009
Literature Search End Date
January 10, 2015
Description of External Review Process
The Pediatric Endocrine Society (PES) codeveloped and endorsed the guidelines.
Specialties Involved
Endocrinology, Nuclear Medicine, Oncology, Otolaryngology, Pathology, Pediatrics, Pediatric Endocrinology, Pediatric Oncology, Pediatric Otolaryngology, Thyroidology, Radiation Oncology, Pediatrics, Pediatrics, Pediatrics, Endocrinology, Oncology
Description of Systematic Review
None of the scientific or medical content of the manuscript was dictated by the ATA. The task force met by conference calls and in person and developed a series of clinically relevant questions pertaining to the management of children with thyroid nodules and DTC. Task force members were assigned to subcommittees structured along the lines of these clinical questions and attempted to answer them using an extensive literature search, primarily focused on studies that included subjects ≤18 years of age, in addition to expert opinion. With contributions from all authors, the document was primarily written by the chair and cochairs (GLF, AJB, and SGW). The Pediatric Endocrine Society (PES) codeveloped and endorsed the guidelines. The final document was approved by the ATA (Board of Directors and membership) and the PES (Drug and Therapeutics Committee and Board of Directors).
List of Questions
43 questions. 34 recommendations. Refer to Guideline.
Description of Study Criteria
Inclusion Criteria: 18 years of age (or less). Exclusion criteria: Nineteen years and older.
Description of Search Strategy
Task force members were assigned to subcommittees structured along the lines of these clinical questions and attempted to answer them using an extensive literature search, primarily focused on studies that included subjects 18 years of age or older, in addition to expert opinion.
Description of Evidence Analysis Methods
Consensus
Description of Evidence Grading
Recommendations were made based upon scientific evidence and expert opinion and were graded using a modified schema from the United States Preventive Services Task Force
Description of Recommendation Grading
Recommendations were made based upon scientific evidence and expert opinion and were graded using a modified schema from the United States Preventive Services Task Force (A, B, C, D, E, F, I).
Description of Funding Source
These guidelines were funded by the ATA without support from any commercial sources. The patient organization, ThyCa: Thyroid Cancer Survivors’ Association, Inc., also contributed an unrestricted educational grant toward the development of the pediatric thyroid cancer guidelines.
Company/Author Disclosures
ATA has a COI Policy. Author disclosures are included.
Percentage of Authors Reporting COI
100