Attention should be focused on family history of thyroid cancer, especially MTC, and on history of exposure to radiation for previous oncohematological diseases. Medical history should be evaluated with peculiar attention to traits and diseases evocative of familial/syndromic forms of thyroid nodules and cancer. Reports suggest that male sex is associated with a higher malignancy likelihood of thyroid nodules.

The objective examination aims at detecting (a) associated lymph node enlargement, (b) signs and dysmorphic features in syndromic patients, (c) signs or symptoms of local compression (dysphagia, dysphonia, discomfort, or shortness of breath), or (d) signs or symptoms of hyperthyroidism.

Palpation of hard and firm nodules or lymph nodes and compression/invasion symptoms are considered indicative of malignancy. Lymph nodal enlargement is of the utmost importance in children as strikingly more common than in adult patients [8, 59] and presents in 80 % of cases [60, 61], although not implying a worse prognosis [62].

Laboratory tests include the measurement of serum TSH, free T4 (fT4), calcitonin, and free T3 (fT3) in case of suspected hyperthyroidism. Most thyroid nodules occur without symptoms of thyroid hormone excess or defect: >90 % of cases are euthyroid, 5 % hypothyroid (mostly subclinically with normal fT4 and elevated TSH), and 1–5 % hyperthyroid. Calcitonin is usually employed as a screening marker for MTC [7]. If its dosage is mandatory in patients with suspect MTC, MEN2 syndromes, and cytology suggestive of medullary neoplasm, its systematical use in all cases of thyroid nodules is debated [63], mostly because of its cost-effectiveness. There is general agreement that calcitonin levels >100 pg/ml are almost certainly indicative of medullary thyroid cancer [64]. Difficulties arise in mild elevations (the 10–100 pg/ml “gray zone”) as calcitonin serum concentration physiologically increases with age and weight, differs according to sex, and may be high also in other conditions (other neuroendocrine cancer, nephropathy, pancreatitis, hypergastrinemia, thyroid autoimmunity, sepsis). In these cases, in order to increase specificity, a confirmatory repeated dosage or a stimulation test (calcitonin dosage 2, 5, and 15 min after pentagastrin 0.5 μg/Kg i.v. bolus) has been suggested [64].

Some ancillary laboratory tests are performed in some specialized/research centers and mostly in adults, as the dosage of thyroglobulin/calcitonin in the washout fluid of neck lymph nodes: these two markers of follicular cancer and medullary cancer, respectively, are sensitive and specific for the early detection of cervical metastases. The test is mostly employed in cases with small thyroid nodules with enlarged lymph nodes [64–66].

Thyroid ultrasound has a key role in the diagnostics of nodules, while I131/Tc99 scintiscan is less extensively employed nowadays with respect to some decades ago. On the other hand, novel techniques, like elastography, are progressively introduced in clinical practice. The employment of other imaging techniques like computer tomography and nuclear magnetic resonance is limited to exceptional cases and to define disease extension or characterize masses of unclear origin.

Guidelines and randomized trials specific for children have not been designed because of the uncommon occurrence of this disease. Although surgery is the primary therapy for pediatric patients with DTC, there is continuing controversy regarding the optimal surgical option (total thyroidectomy, near-total thyroidectomy, subtotal thyroidectomy, or lobectomy) as well as the role of prophylactic central neck dissection. Currently, total or near-total thyroidectomy in pediatric patients with DTC is considered the best approach by most surgeons and according to the American Thyroid Association (ATA) guidelines [9, 16]. Lobectomy alone may be sufficient treatment for small (<1 cm), low-risk, unifocal, intrathyroidal PTC. The facilitation of radioiodine treatment and imaging and the use of serum thyroglobulin as a tumor marker for recurrent/residual disease [94] are considered other practical advantages of extensive surgery. A primary procedure with less than total thyroidectomy has been demonstrated to significantly increase the need for repeating surgery [95]. Moreover, tumor size should not be considered as a determinant for the type of surgery in children [14]. Although TNM scoring system for differentiated thyroid cancer includes age because of its strong prognostic, it is commonly considered to be imperfect in childhood when the risk of recurrence is high [96].

Since lymph node involvement at the diagnosis is common [8, 59], central neck dissection has been recommended, and modified neck dissection should be performed for clinically apparent and biopsy-proven lateral neck disease. Prophylactic lateral neck dissections are not recommended [94]. On the other hand, complications of total thyroidectomy and potential harms of the central compartment dissection such as hypoparathyroidism and injury to the recurrent laryngeal nerve should also be considered. Although these risks are minimized when surgery is performed by an experienced endocrine or pediatric surgeon, a high prevalence of hypoparathyroidism and both temporary and permanent recurrent laryngeal nerve palsy has to be taken into account. Recently, age (<16 years), familial history of thyroid cancer, preoperative gross neck lymph node diffusion, tumor diameter, and extrathyroidal invasion were identified as risk factors for disease-free survival in children with PTC. Preoperative gross lymph node metastasis and distant metastasis at diagnosis were identified as relevant factors for cause-specific survival, suggesting that total thyroidectomy alone could not be considered sufficient in all childhood patients [97].

In general, treatment of MTC consists in total thyroidectomy for both sporadic and hereditary forms associated with prophylactic central lymph node dissection, whereas lateral neck dissection is needed for patients with positive preoperative imaging. When distant metastatic disease is detected at diagnosis, less aggressive surgery might be appropriate in order to preserve speech and prevent morbidity. The improved understanding of molecular basis of MEN2 syndromes and isolated MTC allows to define risk groups for cancer development and recommended timing schedule for prophylactic treatment. The latter is the standard of care in pediatrics, since patients with hereditary forms of MTC can develop metastases before the age of 5 [38, 97–99]. Prophylactic thyroidectomy in MEN is recommended within 1 year of age for patients with 883, 918 RET codon mutations, before 5 years for cases with mutations in codons 611, 618, 620, 634, and before 10 years for those with mutations in codons 609, 630, 768, 790, 791, 804, 891.

Radioactive iodine (RAI or radioiodine 131I) therapy is a mainstay of postsurgical treatment in DTC. 131I has been demonstrated to destroy thyroid tumor cells several decades ago [100]; moreover, a postsurgery 131I uptake by residual thyroid tissue is usually demonstrated. The frequent multifocal disease extension, nodal involvement, and distant metastases in pediatric patients with DTC together with a sodium iodine symporter expression greater than in adult forms, possibly accounting for a more successful treatment [101], are generally considered as factors making RAI a therapeutic challenge. To date, it is generally suggested that most children should be treated with 131I in order to ablate residual disease, reduce the risk of disease recurrence, and positively affect progression-free survival rate, as recently reviewed [14, 94, 95, 101, 102].

In order to obtain 131I uptake by remnant and residual tissue, TSH elevation greater than 30 mU/l is needed. Levothyroxine administration should be discontinued 2–3 weeks in children and 4 weeks in adults before radioiodine administration (“thyroid hormone withdrawal,” THW); alternatively, patients can be treated with 0.7 mcg/kg triiodothyronine for at least 1 month to be discontinued 2 weeks before 131I administration. TSH rise can also be achieved with recombinant human TSH (rhTSH) to be administered on 2 consecutive days. The use of rhTSH is approved in adults; however, it has to be emphasized that, at present, rhTSH use is not approved for children by drug-regulatory agencies in U.S.A. or E.U. Although it has the potential to reduce whole-body radiation exposure associated with 131I therapy and its clinical use has been reported in children with DTC, data showing comparable efficacy to THW are lacking in pediatrics [9, 14, 94, 103].

Main purposes of the use of RAI treatment include therapy of residual microscopic disease, metastatic or unresectable lesions, together with an accurate patient staging by means of 131I whole-body scanning, usually performed within 4–7 days of RAI therapy, for the detection of distant metastases. In addition, the postsurgery ablation of remaining thyroid tissue in the neck (“thyroid remnant ablation”) allows the use of thyroglobulin as a tumor marker during the follow-up. There is no specific recommendation for the timing of 131I after total thyroidectomy; however, it is generally done within 3–6 weeks till 3 months after surgery. 131I administration dosage strategies can be summarized in administering fixed activities (eventually based on the patient’s weight); dosing based on the administered activity that is as high as safely administrable, recently defined as the lowest safe limit administered activities up to 5 mCi/kg (185 MBq/kg) for treatment of distant metastases and DTC recurrence in children; and applying specific activities for tumor ablation, dosimetry, which is suggested to be mainly considered for individuals with lung metastases [14, 104]. The use of pretherapy scans is limited because of its low impact on the decision to ablate and because of 131I-induced stunning phenomenon, defined as a reduction in uptake of the RAI therapy dose induced by a pretreatment diagnostic activity. On the other hand, since it can be difficult to distinguish residual disease from thyroid remnant at post-therapy whole-body scan and when the extent of the thyroid remnant cannot be accurately ascertained from the surgical report or neck ultrasonography, 123I (1.5–3 mCi) or low-activity 131I (1–3 mCi) pretherapy scans may provide additional information [9, 14] in order to distinguish residual disease from thyroid remnant and then to plan more adequate therapeutic strategies.

Risks associated with RAI treatment include second primary malignancies, reproductive risks, pulmonary fibrosis, gastritis, and sialoadenitis. Evidence suggests that RAI does not increase the risk of second neoplasms in children nor long-term effect on female fertility. Given the possibility of cumulative gonadal damage in males, sperm banking should be considered before therapy [14].

Levothyroxine therapy is a fundamental part of the treatment of thyroid carcinoma; it is well recognized that TSH suppression can reduce rates of recurrence for DTC, whereas there is no role for it in MTC. The ATA task force recommends in low-risk adult DTC patients a plasmatic TSH target of 0.1–0.5 mU/l and a more aggressive suppression for high- and intermediate-risk patients, with TSH <0.1 mU/l. Benefits from TSH suppression have been widely reported in adults in terms of decreased progression and recurrence rates and cancer-related mortality. For adults, recommendations state that suppression should be maintained for 5–10 years [9]. On the other hand, specific evidence of benefits from TSH suppression in pediatrics is lacking to date. Moreover, compared with adults, TSH suppression presents peculiar difficulties: actually, in children higher doses of levothyroxine per kg are needed to achieve a complete suppression, and a condition of subclinical iatrogenic hyperthyroidism may impact growth, behavior, and learning ability. Recently, a proposed scheme for children is to initially suppress TSH levels <0.1 mU/l and then allow a TSH rise to 0.5 mU/l once remission is obtained [14, 94].