Table 3.

Overview of recommendations and suggestions in the 2022 European Thyroid Association Guidelines for the management of pediatric thyroid nodules and differentiated thyroid carcinoma.

Location	#	Recommendation or suggestion
[A] Organization of care and goals for pediatric thyroid nodules and thyroid carcinoma
[A2]	1	Thyroid expert team We recommend that a child with suspicion of thyroid cancer and proven DTC or MTC should be referred to an experienced multidisciplinary thyroid team, specifically with experience in pediatric thyroid cancer (4S).
[A3]	2	Goals of therapy for DTC in children We recommend that children with DTC are stratified according to those who may benefit from higher-intensity treatment vs those for whom lower-intensity treatment will suffice. By stratification, the goals of therapy for pediatric DTC (to maintain the high survival rate with low recurrence rate and to minimize adverse effects of treatment) will be reached (4S).
[B] Recommendations and suggestions for the pediatric thyroid nodule
[B2]	3A 3B	Risk of malignancy in thyroid nodule during childhood We recommend thyroid ultrasound to assess the risk of cancer in a thyroid nodule, based on multiple ultrasound characteristics. However, ultrasound alone cannot definitively distinguish a benign thyroid nodule from thyroid cancer. For this reason, in suspect nodules, FNB is recommended (Fig. 1) (2S). The expert panel recommends, in children with thyroid nodule(s), a complete neck ultrasound to evaluate all cervical levels for the presence of lymph node enlargement (4S).
[B5]	4A 4B	Children at high risk for developing DTC We recommend that patients with a high risk of developing DTC (history of radiation exposure to the thyroid or a thyroid cancer predisposition syndromes) should be counseled for surveillance (4S). We suggest that initiation of surveillance and the decision regarding which surveillance modality (neck palpation and optionally neck ultrasound) to use are the result of shared decision-making between the physician and the high-risk patient (4W).
[B6]	5	Diagnostic value of serum calcitonin in a child with a thyroid nodule We suggest that, in selected cases (conditions which suggest MEN2, a positive family history of MEN2 or in case of bulky thyroid disease), measurement of calcitonin may be of additional value for early diagnosis of MTC (4W).
[B8]	6	Molecular testing in FNB specimen We suggest that molecular gene analysis for presence of BRAF V600E mutation in a FNB specimen may be helpful for diagnosis of PTC and therefore may be considered in the diagnostic work-up. The presence of PTC however must be confirmed cytologically or histologically before total thyroidectomy is performed (4W).
[B9]	7A 7B	Role of surgery for benign thyroid lesions We recommend that benign nodules should be followed by serial ultrasound and undergo repeat FNB if suspicious features develop (4S). We suggest hemithyroidectomy for benign nodules, performed by an experienced high-volume pediatric thyroid cancer surgeon, in patients with compressive symptoms, cosmetic concerns, or according to patient/parent preference after counseling of the possible benefits and risks of thyroid surgery (4W).
[B10]	8A 8B	Autonomous thyroid nodules in children We suggest hemithyroidectomy for autonomous nodules during childhood, which must always be performed by an experienced high-volume pediatric thyroid cancer surgeon (4W). We recommend discussion of the advantages and disadvantages of surgery vs radioiodine treatment using shared decision-making in each individual case (4S).
[C] Recommendations and suggestions for the management of pediatric differentiated thyroid carcinoma
[C1]	9A 9B 9C 9D	Pre-operative evaluation We recommend neck palpation, comprehensive neck ultrasonography, and laboratory work-up as minimal pre-operative evaluation measures in the pediatric population. The expert panel suggests further genetic or imaging diagnostics in case of suspicion of familial or extensive disease (4S). We suggest additional pre-operative investigations using MRI or low-dose non-contrast CT in case of bulky disease or suspicion of lung metastases (4W). We recommend confirmation with FNB of suspicious lateral lymph nodes (size, aspect, or ultrasound characteristics) (4S). We suggest assessment of vocal cord function in children with bulky disease pre-operatively (4W).
[C2]	10A 10B 10C	Surgical approach for DTC (Fig. 2) We suggest total thyroidectomy as treatment for children with DTC (3W). See Recommendation 10C for exceptions. We recommend that future studies are conducted that evaluate the impact of limited surgery for pediatric DTC with respect to recurrence and remission rates (4S). We suggest that, in pediatric patients with incidentally found, very small thyroid carcinoma, and non-aggressive histological features, hemithyroidectomy may be considered as therapeutic option (4W).
[C3]	11A 11B 11C	Therapeutic central and lateral lymph node dissection We suggest that prophylactic central lymph node dissection should only be performed in advanced pediatric thyroid cancer (extracapsular extension, vascular invasion, distant metastases). It can be avoided or limited to ipsilateral lymphadenectomy in patients without suspicious features for advanced thyroid cancer on neck ultrasound (4W). We suggest that therapeutic central lymph node dissection is always recommended in pediatric DTC in case of suspicious central lymph nodes based on neck ultrasound or intraoperative assessment, or perioperative visible extracapsular tumor growth (4W). We recommend that therapeutic lateral lymph node dissection is performed in all children with pre-operatively proven lymph node metastases or in case of evident (pathological) lateral lymph node(s). The expert panel does not recommend prophylactic lateral lymph node dissection (4S).
[C4]	12	Surgical complications of thyroidectomy and neck dissection We recommend that all children with DTC should be operated on by high-volume pediatric thyroid cancer surgeons with experience in pediatric thyroid cancer and who are embedded in a center with expertise in the management of DTC (4S).
[C5]	13A 13B	Post-operative staging We recommend that post-operative staging is done using the surgical report, histological report, measurement of Tg, and I-131 post-therapy scintigraphy (4S). We suggest that the AJCC TNM classification system is used to describe the extent of disease in pediatric DTC (4W).
[C6]	14A 14B 14C	I-131 therapy We suggest that I-131 therapy is indicated for all children following total thyroidectomy, for the treatment of persistent locoregional, or nodal disease that cannot be resected for as well as iodine avid distant metastases (M1) (4W). We suggest that, for patients with persistent disease following post-operative I-131 therapy, the decision to pursue an additional course of I-131 therapy should be individualized according to previous response (4W). We suggest that the minimal interval between I-131 treatment in childhood for DTC be recommended to be around 1 year (4W).
[C7]	15	I-131 activity We suggest that an individual patient-based approach is used to calculate the optimal activity of I-131 taking into account the potential side effects of I-131 with increasing activity. The preferred individual administered activity should be discussed in the multidisciplinary tumor board taking the individual characteristics of the patient into account (4W).
[C8]	16A 16B 16C	Preparation of the patient for treatment with I-131 We recommend that TSH stimulation (>30 mI/L) is induced before I-131 therapy in order to facilitate I-131 uptake (4S).We suggest that stimulated TSH can be achieved either using thyroid hormone withdrawal or rhTSH. The expert panel did not reach consensus on the optimal way of preparation. The decision for one against the other is up to the clinical experience of the treating team (3W). We suggest that a low iodine diet for at least 4 days before I-131 therapy may be favorable for iodine uptake (4W).
[C9]	17	Targeted therapy for pediatric DTC We suggest that, in specific cases, treatment with targeted therapy may be considered, but this should preferably only be given in the setting of clinical trials (4W).
[C10]	18A 18B	Somatic molecular testing (in thyroid carcinoma tissue) We suggest that molecular testing in pediatric thyroid carcinoma tissue be recommended in research setting but that the result has currently no consequences for pediatric DTC management (4W). We suggest that for cases with I-131 refractory DTC, molecular testing in pediatric thyroid carcinoma tissue be recommended as the result may have consequences for pediatric DTC management (4W).
[C11]	19A 19B	Treatment for pediatric radiation-induced DTC We suggest that children with radiation-induced DTC undergo total thyroidectomy because of the increased risk for bilateral disease (3W). We suggest that for CCS with DTC, specific medical and psychosocial considerations should be taken into account, requiring an individual treatment and follow-up plan (4W).
[C12]	20	Treatment for DTC in children with genetic syndromes We do not suggest adjustment of treatment or follow-up for children with DTC and DICER1 or PHTS or any other tumor predisposition syndrome (3W).
[D] Surveillance and follow-up of pediatric differentiated thyroid carcinoma
[D1]	21A 21B	TSH levels during follow-up (Fig. 3) We suggest that TSH levels should be kept suppressed with concomitant high-normal values of FT4 until full clinical remission, while a low-normal value of TSH (between 0.3 and 1.0 mU/L)) should be advised thereafter (4W). We suggest measurement of TSH and FT4 to monitor the level of suppression or substitution of the LT4 therapy every 3–6 months during growth and puberty and thereafter once a year (4W).
[D2]	22A 22B 22C	Tg measurement during follow-up We recommend that serum Tg is a reliable marker in the follow-up after treatment for DTC in childhood. The expert panel suggests that serum Tg should be assessed every 6 months during the first 3 years and annually thereafter (4S). We suggest that, in case of circulating TgAbs, these may be measured as ‘alternative’ tumor marker (4W). We suggest that a highly sensitive Tg assay should preferably be used in the follow-up of pediatric DTC patients (4W).
[D3]	23A 23B 23C	Ultrasound during follow-up We recommend follow-up with neck ultrasound in combination with serum Tg measurement for detection of recurrent DTC (2S). We recommend that neck ultrasound is performed by a professional with experience in neck ultrasound in childhood (4S). We suggest that annual neck ultrasound is performed in the first 5 years of follow-up. In low-risk patients, the expert panel suggests, after the first year of follow-up, to only perform neck ultrasound in cases with rising Tg or TgAbs or suspicion of recurrence of disease to avoid false-positive findings (4W).
[D4]	24A 24B	Other imaging modalities (I-131, I-124, I-123, or FDG PET/CT scans) during follow-up We suggest that children with undetectable Tg on LT4 during follow-up after treatment for DTC should not undergo other imaging modalities (I-131, I-124, I-123, or FDG PET/CT scans) (4W). We suggest that, in children with detectable (but not rising) Tg on LT4 and no focus on neck ultrasound, in individual cases, I-123 scanning may be considered. If no source of Tg is found, serum Tg and serum TgAbs must be followed every 3–6 months. In case of further rising Tg or TgAbs, further imaging is indicated (4W)
[D5]	25A 25B	Persistent/recurrent cervical disease We suggest performing neck ultrasound in children with consistently rising Tg on LT4 or TgAbs. In these cases, additional I-123 and/or FDG PET scanning may be considered. Surgery or I-131 therapy is indicated depending on the size, tumor load, and degree of progression (4W). We suggest that empiric I-131 iodine treatment be only recommended if the abovementioned diagnostic modalities have failed to identify a source of rising Tg on LT4 or rising TgAbs (4W).
[D6]	26A 26B 26C	Pulmonary metastases and follow-up We recommend that I-131 is the first-line therapy for patients with pulmonary metastases (4S). We suggest that a pulmonary function test should be performed, before repeated I-131 treatment of patients with diffuse lung metastases (4W). We recommend that in children with a previous history of drugs causing pulmonary toxicity such as bleomycin, I-131 treatment must be given with extra caution given the risk for pulmonary fibrosis (4S).
[D7]	27A 27B	Radioiodine refractory disease We suggest that, when radioiodine refractory disease is suspected, its presence should be thoroughly investigated and confirmed before considering systemic targeted therapy. An observation or wait-and-see strategy may be appropriate (4W) We suggest that targeted therapy should be reserved only for patients with large-volume disease which is significantly progressing on TSH-suppressive therapy and not amenable to surgical approach and should preferably be given in a research setting (4W).
[D8]	28A 28B 28C 28D 28E 28F	Late effects of treatment of DTC We suggest counseling pediatric DTC patients about the risk of developing recurrent laryngeal nerve injury or hypoparathyroidism after thyroid surgery and salivary gland dysfunction after exposure to I-131. In addition, the potential risk of subsequent primary neoplasms after I-131 treatment related to I-131 activity and possible risk for cardiac dysfunction after prolonged TSH suppression should be mentioned (3W) We recommend that the recurrent laryngeal nerve and parathyroid gland function is monitored post-operatively (3S). We suggest that all post-pubertal males who receive I-131 may be counseled upon the possibility of (transient) decreased fertility and semen preservation could be offered (3W). We suggest that all pediatric DTC patients receive additional calcium and vitamin D supplementation therapy for optimal bone mineralization during follow-up (4W). We suggest that all patients with pediatric DTC should be offered psychosocial support (4W). We suggest that future studies should further evaluate the prevalence and clinical significance of diastolic dysfunction in survivors of pediatric DTC after prolonged TSH suppressive therapy (4W).
[D9]	29	Follow-up scheme and transition to adult care We suggest to continue follow-up of children with DTC for at least 10 years; thereafter, the follow-up strategy should be the result of shared decision-making between the physician and the patient (4W).

(S) Strong recommendations are clinically important best practice and should be applied to most patients in most circumstances. (W) Weak statements should be considered by the clinician and will be an applicable best practice only to certain patients or under certain circumstances.

CCS, childhood cancer survivor; DTC, differentiated thyroid carcinoma; FDG PET/CT, [18F] fluorodeoxyglucose positron emissive tomography computed tomography; FNB, fine needle biopsy; I-123, iodine-123; I-124, iodine-124; I-131, iodine-131/radioactive iodine; PHTS, PTEN hamartoma syndrome; Tg, thyroglobulin; TSH, thyroid stimulating hormone