Table 1.

Research questions and conclusions of evidence

Research questions, conclusions of evidence		Quality of evidence
Diagnostics and staging
1. What is the sensitivity and specificity of thyroid ultrasound for distinction of thyroid cancer from a benign thyroid nodule of a child?
Conclusion	The expert panel concludes that specificity and sensitivity of thyroid ultrasound for distinction of thyroid cancer from a benign thyroid nodule in children depends on multiple ultrasound characteristics.	⊕⊕⊕⊖
2. What is the sensitivity/specificity of different suspicious US findings for presence of DTC metastasis to a lymph node?
Conclusion	No evidence was found on suspicious US findings specific to DTC in childhood. The expert panel concludes that the sensitivity/specificity of different suspicious US findings for presence of DTC metastasis to a lymph node may be referred to adult literature.	⊕⊖⊖⊖
3. Will molecular testing in an FNB specimen of a thyroid nodule in a child help you to distinguish it from a benign nodule?
Conclusion	No evidence was found. The expert panel concludes that prospective studies are needed to determine if molecular testing in an FNB specimen of a thyroid nodule in a child helps to distinguish DTC from a benign nodule	⊕⊖⊖⊖
4. Does molecular testing in thyroid carcinoma tissue in a child alter its management?
Conclusion	No evidence was found. The expert panel concludes that current evidence is insufficient to conclude that molecular testing in pediatric thyroid carcinoma tissue has consequences for pediatric DTC management and prospective studies are needed.	⊕⊖⊖⊖
5. What is sensitivity of the different imaging modalities for presence of pre-operative metastasis?
Conclusion	No evidence was found. The expert panel concludes that the sensitivity for neck palpation, comprehensive neck ultrasonography, or laboratory work-up to predict DTC, could not be determined.	⊕⊖⊖⊖
6. Are histopathological criteria related to distant/any metastases?
Conclusion	No evidence was found. The expert panel concludes that current evidence is insufficient to relate histopathological criteria to distant/any metastases and prospective studies are needed.	⊕⊖⊖⊖
7. Which imaging modality is most sensitive for the presence of DTC, post-operatively?
Conclusion	No evidence was found. The expert panel concludes that current evidence is insufficient to state which imaging modality is most sensitive for the presence of DTC, post-operatively.	⊕⊖⊖⊖
8. What is the diagnostic value of serum calcitonin in a child with a thyroid nodule?
Conclusion	No evidence was found. The expert panel concludes that current evidence is insufficient to determine the diagnostic value of serum calcitonin in a child with a thyroid nodule	⊕⊖⊖⊖
9. What is the prevalence of non-clinically relevant thyroid nodules in a child?
Conclusion	The prevalence non-clinically relevant thyroid nodules in a non-childhood cancer survivor cohort of children seem to vary between 0.6 and 2%.	⊕⊕⊕⊖
Treatment
10. What is the difference in outcome of DTC in children treated with a total thyroidectomy vs hemithyroidectomy or vs subtotal thyroidectomy?
Conclusion	Total thyroidectomy may be associated with more recurrence-free survival and disease-free survival.	⊕⊕⊖⊖
11. What is the difference in outcome of DTC in children with microcarcinoma (<1 cm) treated with nodule excision/resection vs subtotal resection or vs hemithyroidectomy?
Conclusion	No studies investigated differences in outcome of patients with TMC treated with total thyroidectomy vs hemi or subtotal thyroidectomy. No differences in disease-specific survival and overall survival between patients with TMC and patients with DTC > 1 cm, although patients with TMC were more often treated with partial thyroidectomy/ lobectomies/isthmusectomies and not followed by RAI.	⊕⊖⊖⊖
12. What is the difference in outcome of DTC in children treated with a (prophylactic) central lymph node dissection vs no central lymph node dissection?
Conclusion	Conflicting results were found. One study suggests that an aggressive surgical approach may both simultaneously decrease the risk of recurrence and improve prognostication in patients with more advanced or aggressive disease. Another study showed no difference in recurrence-free survival between patients treated with LND compared to limited node excision of no LND. However, location of LND was not specified. It remains unclear if these patients underwent prophylactic central lymph node dissection.	⊕⊖⊖⊖
13. Is outcome of microcarcinoma worse in children treated with I-131 vs those not treated with I-131?
Conclusion	No evidence was found. The expert panel concludes that current evidence is insufficient and prospective studies are needed to evaluate outcome of small pediatric DTC not treated with I-131 vs those treated with I-131.	⊕⊖⊖⊖
14. Is the most optimal dose-effect curve of radioiodine with least side effects calculated by body weight/fixed-dose dosimetry?
Conclusion	No evidence was found. The expert panel concludes that current evidence is insufficient and agreed that individual patient-based approach should be used to calculate the most optimal activity of I-131 taking into account the potential side effects of I-131 with an increasing activity. The preferred individual administered activity should be discussed in the multidisciplinary tumor board taking the individuality of the patient into account.	⊕⊖⊖⊖
15. Is rhTSH effective and safe in children during treatment with I-131?
Conclusion	All studies reported TSH levels after rhTSH stimulation of >50mIU. No significant side effects were reported. No studies reported on iodine uptake after rhTSH injection.	⊕⊕⊖⊖
16. What is the difference in outcome in children with measurable but not rising Tg after treatment for DTC? (incomplete biochemical response with I-131 vs a wait-and-see approach)
Conclusion	No evidence was found. The expert panel concludes that current evidence is insufficient and prospective studies are needed to evaluate outcome in children with an incomplete biochemical response treated with I-131 compared to a wait-and-see approach.	⊕⊖⊖⊖
17. What is the difference in outcome in children with recurrent disease/progressive thyroid cancer treated with additional I-131/surgery/other vs a wait-and-see approach?
Conclusion	No evidence was found. The expert panel concludes that current evidence is insufficient and prospective studies are needed to evaluate outcome in children with recurrent disease/progressive thyroid cancer treated with additional I-131/surgery/other vs a wait-and-see approach.	⊕⊖⊖⊖
18. What is the difference in outcome of DTC in children treated with different treatment than surgery and I-131?
Conclusion	Based on case reports, targeted therapy may play a role in the management of disease in very rare cases of the pediatric patient with progressive I-131-refractory PTC, for which no standard therapy exists.	⊕⊖⊖⊖
Follow-up
19. What is the sensitivity/specificity of neck ultrasound for recurrent DTC in follow-up of children who have been treated for DTC?
Conclusion	The sensitivity and specificity of thyroid ultrasound for recurrent DTC in follow-up of children who have been treated with total thyroidectomy and radioiodine therapy for DTC are 85.7 and 89.4% respectively.	⊕⊕⊕⊖
20. What is the sensitivity of I-124, I-123, as well as FDG PET/CT for DTC/thyroid rest or recurrent disease in follow-up of children who have been treated for DTC?
Conclusion	No evidence was found. Prospective studies are needed to determine the sensitivity of radioiodine imaging and FDG PET/CT for the detection of persistent or recurrent disease in children who have been treated for DTC.	⊕⊖⊖⊖
21. What are the late effects of treatment of DTC? (cardiac late effects, salivary glands, psychosocial, bone, female fertility)
Conclusion	Cardiac dysfunction: in 21.2% of asymptomatic survivors, diastolic dysfunction was found. Salivary gland dysfunction: in 1.9–47.6 and 35.5% of the DTC survivors, salivary dysfunction and xerostomia were found, respectively. Quality of life: no differences were found in the course of life questionnaire between DTC survivors and two non-affected groups (non-affected with cancer and other CCS). Also, on most quality-of-life subscales, score of DTC survivors and controls did not differ significantly. However, more physical problems, more role limitations due to physical problems, and more mental fatigue were described by DTC survivors. Bone mineral density: no differences were found with respect to BMD and Z scores at any site evaluated by DXA and in bone microstructure parameters between DTC survivors and controls. However, calcium-D3 medication has a beneficial effect on BMD. TSH-suppressive therapy does not affect BMD in women treated for DTC at young age, at least after 10 years of follow-up. Female fertility: no major abnormalities in reproductive characteristics and in predictors of ovarian failure in female survivors of DTC who received I-131 treatment during childhood were reported.	⊕⊕⊕⊖
22. Is presentation, outcome, and/or disease course of DTC in children with genetic syndromes different than in children without genetic syndromes for which treatment and/or follow-up should be adjusted?
Conclusion	In children DICER1 or PTHS, DTC does not seem to have a more aggressive presentation, outcome, and disease course.	⊕⊖⊖⊖
23. Is presentation, outcome, and/or disease course of DTC in children with a history of radiation exposure different than in children without a history of radiation exposure for which treatment and/or follow-up should be adjusted?
Conclusion	Presentation: CCS with subsequent DTC tended to have on average smaller tumors and might have more often bilateral disease. Disease course: inconsistent findings about difference in tumor characteristics (ETE and LNM) were reported. ETE and LMN might be more frequently found in radiation-induced thyroid tumors in children diagnosed in the Chernobyl region. Outcome: no significant differences were found between CCS with subsequent DTC and controls in the occurrence of surgical complications, recurrence rate or disease-related death.	⊕⊖⊖⊖

CCS, childhood cancer survivors; DTC, differentiated thyroid carcinoma; LND, lymph node dissection; PTC, papillary thyroid carcinoma; PTHS, PTEN hamartoma tumor syndrome; rhTSH, recombinant TSH; TSH, thyroid-stimulating hormone.

The modified GRADE system was used to grade the quality of evidence: high (RCT evidence/meta-analysis –high-quality evidence (⊕⊕⊕⊕)); level 2: moderate (intervention short of RCT or large observational studies – moderate-quality (⊕⊕⊕⊖)); level 3: low quality (case–control studies, case series – low-quality (⊕⊕⊖⊖)); levels 4: very-low quality (case reports, expert opinion – very-low-quality (⊕⊖⊖⊖)) (9).