Thyroid nodules and differentiated thyroid cancer.

Thyroid Cancer Szinnai G (ed): Paediatric Thyroidology. Endocr Dev. Basel, Karger, 2014, vol 26, pp 183–201 (DOI: 10.1159/000363164)

Thyroid Nodules and Differentiated Thyroid Cancer Andrew J. Bauer The Thyroid Center, Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia, and Department of Pediatrics, Perelman School of Medicine, The University of Pennsylvania, Philadelphia, Pa., USA

Abstract

The incidence of both thyroid nodules and thyroid cancer in pediatric patients has increased over the last several decades [1, 2]. This change is influenced by several factors, to include, but not limited to, the geographic region and status of iodine sufficiency within the population, access to the health care system and, perhaps most significantly, the increased use of radiological imaging. Thorough evaluation of a thyroid nodule includes complete review of the patient’s medical and family history, followed by thyroid and neck ultrasound and fine-needle aspiration (FNA) biopsy of nodules found to have concerning sonographic features. Similar to adults, the majority of nodules are benign. However, there is a 3- to 5-fold higher risk that a nodule found in a pediatric patient, defined as a patient ≤18 years of age, will be malignant when compared to an adult, i.e. 20–30 versus 5–10%, respectively [3, 4]. Differentiated thyroid

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The incidence of thyroid nodules and thyroid cancer has increased over the last several decades. This change is influenced by several factors, to include the status of iodine sufficiency, access to the health care system and, perhaps most significantly, the increased use of radiological imaging. Thorough evaluation of a thyroid nodule includes review of the patient’s medical and family history, followed by thyroid ultrasound and fine-needle aspiration biopsy. Similar to adults, the majority of nodules in children are benign; however, there is a 3- to 5-fold higher risk that a nodule found in a pediatric patient (≤18 years) will be malignant when compared to an adult. Differentiated thyroid carcinoma (DTC) is the most common malignancy with approximately 90–95% being papillary thyroid carcinoma and the remainder follicular thyroid carcinoma. With proper evaluation and management, the prognosis for pediatric patients with DTC is excellent; however, the risk of treatment complications and recurrence is relatively high. The development of pediatric specific guidelines for the evaluation and management of thyroid nodules and DTC as well as the creation of centers with surgical and medical expertise is crucial in order to optimize care and gain a better understanding of factors that © 2014 S. Karger AG, Basel impact disease-specific morbidity.

Table 1. Risk factors for the development of thyroid nodules and/or DTC Demographic risk factors Female gender Adolescence Family or personal history Iodine deficiency [17] Autoimmune thyroid disease [8, 21] Familial multinodular goiter [17] Familial nonmedullary thyroid cancer [10, 11] Exposure to radiation [22] Syndromes associated with increased risk McCune-Albright syndrome [12] PTEN hamartoma syndrome [13–15] Carney complex [16] Familial adenomatous polyposis [18–20] DICER1 PPB familial tumor predisposition syndrome [23, 24] PTEN = Phosphatase and tension homolog; PPB = pleuropulmonary blastoma.

carcinoma (DTC) is the most common malignancy with approximately 90–95% being papillary thyroid carcinoma (PTC) and the remainder follicular thyroid carcinoma (FTC). With proper evaluation and management, the prognosis for pediatric patients with DTC is excellent; however, the risk of treatment complications and recurrence is relatively high. The development of pediatric specific guidelines for the evaluation and management of thyroid nodules and DTC as well as the creation of centers with surgical and medical expertise are crucial in order to optimize care and gain a better understanding of factors that impact disease-specific morbidity.

The majority of pediatric patients are asymptomatic at the time that a thyroid nodule is discovered either by physical examination or as an incidental finding during nonthyroid-related head and neck radiological imaging. The prevalence data is not very robust; however, estimates predict that approximately 1.5% of pediatric patients have a thyroid nodule based on routine physical examination [5, 6] while up to 18% of pediatric patients have a thyroid lesion based on non-thyroid-related, head and neck radiological examination [7]. Several risk factors are associated with an increased risk of developing a nodule, to include: female gender, adolescence, a personal history of autoimmune thyroid disease [8] and a history of exposure to ionizing radiation, most commonly associated with treatment of a nonthyroid malignancy. Several syndromes are also associated with an increased risk of developing thyroid nodules and/or thyroid carcinoma (table 1).

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Bauer Szinnai G (ed): Paediatric Thyroidology. Endocr Dev. Basel, Karger, 2014, vol 26, pp 183–201 (DOI: 10.1159/000363164)


Presentation and Prevalence

Within several of these populations, there is an ongoing debate whether patients within these subpopulations should undergo serial surveillance ultrasound (US) imaging. While the incidence of disease is increased, the frequency of surveillance for the majority of these syndromes has not been adequately defined. The balance between the benefit of early detection and the risk of unnecessary procedures and undue stress and anxiety to the patient and family must be thoughtfully considered. This is particularly salient for patients with autoimmune thyroid disease where the risk of developing a thyroid malignancy appears to be low while the heterogeneous echotexture found on US is high suggesting that routine screening may result in an excess number of procedures for a low yield of finding a malignancy. In contrast, US surveillance for patients with a history of radiation exposure [9], as well as a history of familial nonmedullary thyroid cancer, may be associated with earlier detection of disease. In familial nonmedullary thyroid cancer, most commonly defined as having 2 or more first-degree relatives with PTC or FTC, surveillance US starting within the pediatric age may be associated with earlier diagnosis and a lower rate of extrathyroidal extension [10, 11].

Similar to DTC in the adult population, activation of the RAS-RAF-MEK-ERK signaling pathway is common and appears to play a critical role in thyroid tumorigenesis [25–27]. However, in contrast to adults where BRAF mutations are the most common identifiable genetic abnormality, mutations in RET/PTC rearrangements appear to be the most common genetic abnormality found in both sporadic and radiation-induced thyroid cancer of childhood [28, 29]. In children and adolescents, limited data suggests that BRAF mutations may be detected in less than 5% of pediatric PTCs [30]. The explanation for why a thyroid nodule found in a child or adolescent carries an increased risk of harboring a malignancy, as well as why children and adolescents have low disease-specific mortality despite presenting with regionally invasive disease, is not understood. The contribution of the growth-promoting microenvironment of childhood cannot be overlooked and is supported by reports showing increased expression of insulin-like growth factor-1, its receptor [31] and nuclear Ki-67 (a marker of cell proliferation) in thyroid tumors from pediatric patients [32]. The only well-established and predictive risk factor for developing DTC is previous exposure to ionizing radiation. Survivors of childhood cancer who received head and neck irradiation during treatment of Hodgkin’s or non-Hodgkin’s lymphoma or central nervous system tumors are at greatest risk [33, 34], with a linear relationship between 0.1 and 15 Gy and an estimated relative risk of 1.3/Gy within this range. The peak relative risk of radiation-induced thyroid cancer is approximately 14.6-fold (95% confidence interval, 6.8–31.5) after exposure to a maximum of 20 Gy [33, 35]. The risk decreases as the dose exceeds 20 Gy as higher doses induce a killing and sclerosing effect

Thyroid Nodules and Differentiated Thyroid Cancer Szinnai G (ed): Paediatric Thyroidology. Endocr Dev. Basel, Karger, 2014, vol 26, pp 183–201 (DOI: 10.1159/000363164)

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Pathogenesis

[33, 35, 36]. Female gender, age at the time of exposure and time since exposure are associated with an increased excess absolute risk [33]. The younger the age at the time of exposure, the shorter the latency to develop a thyroid malignancy [36]. While radiationsparing protocols have been implemented in the treatment of a variety of nonthyroid malignancies, as well as in the preparation for bone marrow transplantation, there is a significant number of patients previously treated who require life-long surveillance as the latency to develop thyroid cancer spans over 3–4 decades of life [33, 35, 36]. The Chernobyl accident provides the most powerful reminder of the interaction of iodine deficiency and the increased incidence of thyroid malignancy when persons are exposed to internal ionizing radiation [37]. Perhaps the most notable lesson to remember from this unfortunate accident is that the use of cold iodine prophylaxis can effectively prevent the risk of developing radiation-induced thyroid malignancy [38]. The higher thyroid cell proliferation index [32], as well as an increased expression of the sodium/iodide symporter [39], may explain why children are at an increased risk of developing thyroid nodules and thyroid cancer after exposure to either radiation from medical evaluation and/or treatment or environmental radioiodine (radioactive iodine, RAI) [40]. Alterations of thyrotropin (TSH) levels and the TSH receptor pathway are additional mechanisms of thyroid nodular disease. Hyperthyrotropinemia is positively correlated with iodine deficiency [41] and may be a contributor to altered thyrocyte growth, nodule formation and, potentially, thyroid tumorigenesis [42]. Lastly, somatic mutations in the TSH receptor and GNAS genes are associated with the development of autonomous nodules and diffuse or nodular hyperthyroidism [43], and, although infrequent, autonomous nodules may be associated with PTC [44].

The differential diagnosis of a mass in the anterior, central neck includes benign as well as malignant lesions. For lesions that are extrathyroidal, the differential diagnosis is similar to that of adults; however, the prevalence of congenital, nonmalignant malformations is greater in the pediatric age group. The most common extrathyroidal lesions include thyroglossal duct cysts, followed by branchial cleft cysts, dermoid and epidermoid cysts and cervical thymic tissue [45]. Thyroglossal duct cysts are usually found within 1 cm of the midline. Ectopic thyroid tissue may be found in the thyroglossal duct cyst and may be the only thyroid tissue, with no eutopic tissue found on radiological or radioisotope imaging. On rare occasions, PTC may be found within the thyroglossal duct cyst, and, in up to 40% of patients with a eutopic gland, there may be a primary or additional lesion found within the thyroid [46]. Branchial cleft anomalies from the 3rd and 4th arch are typically located in the lateral neck, although, with abscess formation, they may extend medially and even extend into the thyroid, most commonly the left side [47, 48]. Identification of the sinus and fistula tract, with

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Differential Diagnosis

a

b

Thyroid

ITTR

c

d

Hassall’s corpuscles

subsequent resection, is essential in order to avoid recurrent suppurative thyroiditis and/or recurrent neck abscess [47, 48]. For intrathyroidal lesions the differential diagnosis includes branchial arch anomalies, ectopic thymic tissue, colloid cysts (pure or mixed solid-cystic), follicular adenoma, and thyroid malignancies, FTC, PTC and medullary thyroid carcinoma (MTC). Hyperfunctioning or autonomously functioning nodules are often solitary with increased vascularity on Doppler US imaging with symptoms ranging from subacute to overt hyperthyroidism [49]. In adolescent patients, there may be a discrepancy between thyroid function abnormalities and clinical signs, and disruptive symptoms such as anxiousness, difficulty concentrating and difficult sleeping may be present. In these cases, TSH may be suppressed or be in the low-normal range with triiodothyronine and thyroxine at the upper end of the normal range or above. Increased uptake with unifocal distribution on radionucleotide scan may be used to confirm the diagnosis. The last benign lesion to consider is unique to the pediatric population: ectopic intrathyroidal thymic remnants (ITTRs). These benign lesions are most frequently found as an asymptomatic nodule discovered incidentally during head and neck radiographic imaging or during thyroid US performed for evaluation of congenital hypothyroidism. On US ITTRs are hypoechoic with punctate, bright internal echoes (‘stipulated’), features that may mistakenly be interpreted as microcalcifications raising concern for malignancy (fig. 1) [7, 50]. Careful US interrogation of the thyroid


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Fig. 1. Intrathyroidal thymic remnant. a A hypoechoic, well-demarcated thyroid nodule with iso- to hyperechoic foci in a 2-year-old. b Magnified view of the same lesion (*) with a lesion adjacent to the thyroid (+) demonstrating similar features. c Sagittal view of the thyroid (*) demonstrating unusual shape. d Histology of the lesion showing normal thymic tissue (*) embedded within a normal-appearing thyroid.

will often reveal an unusual shape to the lesion with extension to and often beyond the edge of the thyroid gland. Additional thymic tissue may be found adjacent to the thyroid (fig. 1b, c), and/or the ITTR may extend in a caudal direction toward adjacent cervical thymic tissue. On occasion, the lesions may be bilateral. These US characteristics are pathognomonic and, if identified, close US surveillance may be pursued rather than FNA and/or surgical resection. While the maximum length of surveillance in the literature is 34 months [51], the rarity of the lesion in adult series suggests that ITTRs follow an expected course of involution. If FNA is performed, small, round monotonous lymphoid cells will be found with the absence of thyroid follicular cells [52]. Flow cytometry of the FNA aspirate will confirm lymphoid cell lineage [52]. The differential diagnosis of malignant lesions in the thyroid is mostly confined to primary thyroid malignancy. More than 90% of malignant lesions are PTC or follicular variant PTC, 5–10% are FTC, and MTC comprise the remaining malignant lesions, the latter most frequently associated with multiple endocrine neoplasia type 2 (MEN2) [53]. Sporadic MTC, dedifferentiated and anaplastic thyroid cancer are nearly exclusive to the adult population. The only exception is MEN2B where sporadic disease associated with de novo mutations is common. MEN2B is associated with specific physical examination features, most notably long-narrow facies, marfanoid body habitus and mucosal neuromas of the lips, tongue, conjunctiva, urinary and gastrointestinal tracts [for further discussion, see the paper by Viola et al., this vol., pp. 202–213; 54]. Last, intrathyroidal thymomas (spindle epithelial tumor with thymus-like differentiation [55]) and teratomas [56] have been reported in the pediatric age group, and rarely, the thyroid gland may be a target for metastasis from nonthyroid malignancy.

History and Physical Examination The majority of pediatric patients are asymptomatic at the time of diagnosis with the thyroid mass discovered incidentally by the patient, parent or health care provider. With the more frequent use of radiological imaging there has been an increased number of patients referred for evaluation of incidentally discovered thyroid nodules found during US, computed tomography (CT) or magnetic resonance imaging (MRI) of the head and/or neck [7]. While a significant number of these referrals are often for low-risk lesions (purely cystic), there is no evidence in the pediatric literature to suggest that an incidentally discovered thyroid nodule is associated with a lower risk of malignancy. As previously mentioned, there are several risk factors associated with an increased risk of developing a thyroid nodule and DTC (table 1), and a query of these factors should be incorporated into the screening interview.

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Diagnostic Evaluation

The physical examination should focus on the thyroid gland as well as the cervical lymph nodes. Visual inspection with the neck extended is the most important initial maneuver for the thyroid examination, followed by palpation for the presence of a nodule(s), with notation made in regard to the size and symmetry of the thyroid gland as well as the texture and feel of the gland and/or nodule(s). Determination of abnormal cervical adenopathy, particularly in cervical regions II, III, IV, V and VI, is an essential aspect of the examination, looking for asymmetric lymph node enlargement, hard texture and absence of mobility, features associated with malignant transformation. The presence or absence of physical examination features associated with the aforementioned syndromes (table 1) should also be documented. The finding of macrocephaly, lipomas and genital freckling (PTEN Hamartoma Tumor syndrome), lentigines (Carney complex, familial adenomatous polyposis), café-au-lait macules (McCune-Albright syndrome) and others are important clues to determine the risk and appropriate surveillance for thyroid nodules and/or DTC.

Radiolological Imaging Thyroid US is the most efficient initial method for assessing thyroid tissue morphology. US can detect lesions as small as 2–3 mm in size and provides information on the size, location, echogenicity, blood flow, multiplicity and potential involvement of


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Laboratory Tests There are few laboratory tests that help discern the risk of malignancy of a thyroid nodule. The one exception is a suppressed TSH level, a finding that is consistent with the diagnoses of an autonomously functioning thyroid nodule. Autonomous nodules are typically associated with a lower risk of malignancy; so, assessing the TSH may change the approach to management and is a worthwhile step in the evaluation process prior to pursuing FNA and/or deciding on treatment (fig. 2). The utility of measuring preoperative thyroglobulin (TG) and calcitonin has also been explored. In adults, preoperative TG levels are generally considered to have low specificity in estimating the risk of malignancy; however, TG levels above 300–400 ng/ ml may help distinguish between follicular adenoma and carcinoma [57]. Similar data has not been examined in the pediatric population. There are conflicting recommendations in regard to obtaining serum calcitonin levels in patients with sporadic thyroid nodules. The European thyroid cancer task force recommends routine screening of serum calcitonin [58]; however, the American Thyroid Association guidelines do not [59]. For patients with a family history of MEN2A, or with physical examination features of MEN2B, a calcitonin and carcinoembryonic antigen determination should be sent concurrently with RET protooncogene testing [54]. For all other pediatric patients with a thyroid nodule, a random serum calcitonin measurement is very unlikely to be of diagnostic utility due to the low incidence of sporadic MTC. One must also be aware that basal calcitonin levels prior to the age of 3 years are elevated after which they trend into the adult range [60].

a

Microcalcifications

c

b

d

Hilum

e

f

g

h

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Fig. 2. US features correlating with thyroid carcinoma. a Hypoechoic, large, left thyroid nodule with hyperechoic foci (microcalcifications). b Sagittal view showing ill-defined borders with increased blood flow (c). d Diffuse, infiltrative form of PTC with scattered microcalcifications and no nodule (diffuse sclerosing variant PTC). e Normal lymph node with fusiform (oblong) shape and hilum with central flow (f). g Abnormal lymph node (PTC) with rounded appearance, cystic areas, microcalcifications and peripheral blood flow (h).

Table 2. US features concerning malignancy US features of thyroid nodule Solid Hypoechoic Increased intranodular blood flow Irregular or interdigitating border Microcalcifications

regional lymph nodes [61]. There are several US features that suggest the malignant potential of a thyroid nodule (table 2; fig. 2) but few that are specific enough to provide a definitive diagnosis. The two exceptions are small, purely cystic lesions, which are nearly without exception benign, and lesions with calcifications (micro or macro) that carry a high risk of malignancy (both PTC and MTC) [62–65]. In children, the size of the nodule has less diagnostic utility in predicting malignancy [64] and must be interpreted in relation to the age and height of the patient as the thyroid does not reach adult size until mid to late puberty [66]. A previous history of exposure to ionizing radiation may be associated with a smaller, atrophic gland as well as an increased risk of malignancy. So, the size of the nodule must also be interpreted in the context of risk factors (table 1). Last, PTC may present with a diffusely infiltrative form where a distinct nodule may not be present. This is typically associated with the diffuse sclerosing variant of PTC. On examination the thyroid will be enlarged and hard, and typically there will be multiple abnormal lymph nodes in the lateral neck. On US the gland will be enlarged with hyperechoic foci (microcalcifications) throughout (fig. 2d). In addition to the physical examination, complete radiological evaluation of a thyroid nodule must include evaluation of lymph nodes in central (level VI) and lateral (levels II, III, IV and V) neck regions [67]. This information aids in the diagnosis and ultimately serves as preoperative staging for patients ultimately diagnosed with thyroid cancer. Up to 70–80% of pediatric patients with PTC have metastasis to the regional lymph nodes at the time of presentation [68–71]. Discovery of cervical lymph nodes with features suggestive of metastatic disease (table 2; fig. 2) increases the likelihood of malignancy for the primary thyroid lesion [64, 72]. CT or MRI of the neck may increase the sensitivity of identifying level VI disease preoperatively [73]. FNA should be pursued to confirm lymph node metastasis, most importantly in the lateral neck (levels II, III, IV and V), with saline washout for measurement of TG from the FNA lymph node sample if cytology is equivocal [74].


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US features of lymph node Rounded shape Peripheral blood flow Cystic regions Loss of hilum Microcalcifications

Thyroid nodule

Radionuclide uptake and scan Consider FNA Lobectomy

Suppressed TSH

FNA under US guidance

Repeat FNA in 6 months sooner if clinical suspicion for cancer is high

Repeat US in 6–12 months

Repeat US in 6–12 months

Nodule stabl

Nodule stable and/or reassuring by FNA

e

Benign

Atypia of undetermined significance

No risk factors (table 1 and 2)

or s ing ure ow feat gr le US du in No nge a ch

Inadequate

Repeat US every 1–2 years

Follicular neoplasm or

Total thyroidectomy

Risk factors

Lobectomy

Repeat FNA in 6–12 months

Consider repeat FNA and/or surgery

Suspicious for malignancy or malignant

Benign

Check thyroid function in 4 weeks and follow clinically

Malignant

Completion thyroidectomy

Fig. 3. Diagnostic evaluation and treatment of a thyroid nodule.

Fine-Needle Aspiration Biopsy Once a nodule(s) has been identified, the next step in the evaluation is FNA. The use of conscious sedation for younger children, and anxiolytics for adolescents, is appropriate but must be performed in a setting with fully qualified and credentialed pediatric providers. US-guided FNA [75] and cytological confirmation of sample adequacy at the bedside decrease the rate of nondiagnostic sampling. The Bethesda System for Reporting Thyroid Cytopathology is the most commonly used classification scheme to define the risk of malignancy in an FNA sample [76]. The risk of malignancy was defined from adult patient samples but is generally accepted as applicable to the pediatric population. The ‘indeterminate’ category poses the greatest clinical challenge across all age groups; however, in contrast to adults,

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The use of additional radiological modalities, to include radionuclide scanning, positron emission tomography and others, is rarely helpful in diagnosing thyroid malignancy, exposes the patient to additional radiation and, thus, should be avoided. The only exception is in patients with a thyroid nodule and suppressed TSH where radionuclide scanning should be pursued to confirm the presence of an autonomously functioning thyroid nodule.

there are few studies that have explored molecular markers to improve the specificity, positive predictive value and negative predictive value of FNA in patients ≤18 years of age. A recent study by Monaco et al. [77], examining 66 patients ≤21 years of age with histological follow-up and molecular analysis, reported a higher risk of malignancy in FNA samples classified as a ‘follicular lesion with undetermined significance’ or ‘follicular neoplasm’ and having a HRAS, NRAS or BRAF mutation, RET/PTC1 or PAX8/PPARγ rearrangement, 5–15% versus 28% for follicular lesion with undetermined significance and 15–30% versus 58%, respectively. With a lack of established cellular or biochemical markers to more accurately identify benign from malignant disease in the indeterminate classification category, in a pediatric patient with follicular lesion with undetermined significance or follicular neoplasm, most clinicians advocate for lobectomy/isthmusectomy or total thyroidectomy based on clinical criteria such as age of the patient, nodule size and distribution (unilateral vs. bilateral), US features, family history and/or history of radiation exposure (environmental or medical). Unfortunately, this approach results in a significant number of patients either referred for completion thyroidectomy when DTC is found on histological examination or placed at undue surgical risk when the final histology reveals benign disease.

Iodine-131 Therapy Approximately 6–8 weeks after surgery, patients are evaluated by a stimulated TG and 123I diagnostic whole-body scan (DxWBS). Two to three weeks before the DxWBS, thyroid hormone replacement is withheld, and the patient is placed on a


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Treatment of Differentiated Thyroid Cancer Treatment of thyroid cancer in children is similar to that in adults, with surgical resection followed by RAI therapy for the majority of patients. For patients with PTC confirmed by FNA, total thyroidectomy is the recommended surgical approach due to an increased likelihood for multifocal and bilateral disease [69, 70, 78–80]. Due to the high rate of metastasis to lymph nodes in the central neck, prophylactic central neck dissection should be strongly considered in an effort to decrease the risk of persistent or recurrent disease [69, 79, 81]. Lateral neck dissection should only be pursued after FNA confirmation of metastatic disease. All thyroid surgeries should be performed by a high-volume surgeon, defined as a surgeon who performs 30 or more thyroid surgeries per year, the majority for thyroid cancer, at a center capable of providing the full complement of pediatric skilled ancillary support [82]. This approach is associated with a low risk of permanent complications and provides distinct advantages for follow-up, most importantly allowing for the most efficient use of RAI therapy and improving the sensitivity of detecting residual or persistent disease on posttreatment scans [4–6, 8, 17]. The most frequent complications of aggressive thyroid surgery are permanent hypoparathyroidism and recurrent laryngeal nerve damage.

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low-iodine diet, allowing for optimal absorption of the 131I. A serum TSH determination is performed before the administration of 131I with a goal of achieving a TSH of at least 30 mU/l. Because of the associated decreased quality of life, the concern that an elevated TSH level may serve as a proliferative factor for any remaining malignant thyroid cells, and an effort to decrease exposure of nonthyroid tissues to 131I, recombinant human TSH (rhTSH) is frequently used rather than thyroid hormone withdrawal. In low-risk adult patients the use of rhTSH appears to be as effective as thyroid hormone withdrawal in achieving remission [83]. The ability to achieve adequate TSH elevation using rhTSH has been studied in children using similar dosing (0.9 mg × 2 doses given 24 h apart) [84]; however, to date efficacy studies in the pediatric population have not been reported. While a subset of pediatric patients stand to benefit from the selective use of rhTSH, prospective studies are needed to define a low-risk population and to more adequately determine the safety and efficacy of rhTSH in the pediatric population. There is no consensus on a standardized dose of 131I in children. 131I activity is frequently dosed empirically, given as a fraction (child’s weight in kilograms divided by 70 kg) of a typical adult dose or based on weight (1.0–1.5 mCi/kg) or body surface area. The dose is then adjusted based on the stimulated TG level and the 123I DxWBS uptake and images (i.e. thyroid bed uptake only vs. evidence of regional or distant metastasis). For younger patients and patients with known pulmonary metastasis, dosimetry may be preferable, either lesion based, calculated to maximize the likelihood of tumor control or based on the maximum activity that can be administered to limit damage to normal tissue (bone marrow and lung) [85–87]. A low-iodine diet is instituted prior to administration of 131I in an effort to improve sensitivity of the WBS as well as efficacy of 131I dosing if RAI treatment is indicated. If bulky cervical disease is found on either surveillance neck US, anatomic imaging (CT or MRI) or during review of the DxWBS, surgical resection should be strongly considered prior to administration of a 131I treatment dose. The addition of hybrid single-photon emission CT with WBS imaging provides greater specificity for localizing persistent disease which may be amenable to surgical resection [88, 89]. A posttreatment WBS should be obtained 5–8 days after the 131I treatment dose has been administered. There are short- and long-term side effects of 131I that need to be considered when deciding who may benefit from 131I and what dose should be administered. The most common postingestion side effect is nausea, which may be avoided with antiemetic therapy. Within several days of therapy, patients may also experience mild salivary gland discomfort. Salivary gland dysfunction may also result in dry mouth (xerostomia), altered taste and increased caries. Only a small percentage of patients develops permanent salivary gland dysfunction; however, for patients that experience 131Iinduced salivary dysfunction, it may take up to 15 months for symptoms to resolve [90].


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Bone marrow suppression and gonadal toxicity may also occur, with an increased incidence at higher 131I doses and if repeated doses are administered within a relatively short period of time [91]. Bone marrow toxicity typically normalizes by 2 months without intervention. Gonadal toxicity may be associated with menstrual irregularities and decreased spermatogenesis. While there does not appear to be an increased incidence of infertility or birth defects, sperm banking should be considered for older adolescents anticipated to need higher cumulative doses of 131I. Male patients should avoid attempts at conception for at least 4 months, and females for at least 1 year, after 131I administration [92–94]. Pediatric patients with pulmonary metastasis are at an increased risk of developing pulmonary fibrosis. Serial pulmonary function testing and cross-sectional anatomic imaging should be used to follow these patients and, if available, dosimetry should be used to calculate 131I dosing [95]. Within this population one must be aware that at least 1/3 of pediatric patients with pulmonary metastasis may develop stable, but persistent disease that will not respond to repeat doses of 131I [96]. Despite the inability to achieve remission in this subpopulation, patients with stable, persistent pulmonary disease most commonly experience decades-long survival. Patients must be followed with serial, surveillance TG levels as well as repeat imaging (CT and/or DxWBS) to ensure stability. Recent data shows that the cidal effect of the initial 131I treatment, interpreted as the TG nadir, may be delayed for 18 months or longer with decreasing TG levels and decreased evidence of disease by imaging years after the last dose of RAI has been administered [97, 98]. Over the last decade there has been increasing concern over potential 131I-induced nonthyroid second primary malignancy with subsequent efforts to define which patients may or may not benefit from 131I therapy. Many of the second primary malignancies are in tissues with active absorption of 131I (salivary glands) or in nonavid tissues passively exposed to 131I during physiological clearance (bone marrow, colon, bladder and others) [79, 99, 100]. In adults, there is general agreement that patients with unifocal PTC, 1 cm in size or smaller, and without evidence of metastasis do not benefit from 131I treatment [59]. In children and adolescents, there are similar efforts to define low-risk patients that may not benefit from RAI; however, to date, there is no consensus on which children should be considered low-risk cases. Despite a lack of consensus, there are at least 2 clinical scenarios where the benefit for 131I therapy may be less than the risk. The first situation is for patients with an incidentally discovered micro-PTC after surgical resection for nonmalignant disease (Graves’ disease). The second situation is for patients with an undetectable, postsurgically stimulated TG and no evidence of focal uptake on postoperative staging 123I DxWBS. Patients with the latter scenario have achieved the goal of therapy without 131I and should enter into surveillance rather than being unnecessarily exposed to 131I. There are likely to be other groups within pediatrics where 131I treatment could be delayed and/or withheld, and further consideration and discussion would be beneficial.

Treatment Summary The prognosis for children diagnosed with differentiated cancer (PTC or FTC) is excellent with low disease-specific mortality when compared to other pediatric cancer types as well as adult patients with a similar extent of disease [26, 53, 79]. However, even with aggressive initial therapy, up to one third of the patients may experience recurrence of disease at times 30 or more years after diagnosis. Pregnancy appears to be a time of increased risk [59, 79, 104, 105]. For the majority of patients, total thyroidectomy followed by evaluation for the administration of 131I is the most sensible approach to initial treatment with a 10-fold increase in disease-free survival when compared to nontotal thyroidectomy [70]. With the increased concerns over second primary malignancy in the thyroid cancer population, efforts should be made to stratify which patients may or may not benefit from 131I therapy. With rare

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Thyroid Hormone Suppression and Surveillance All children with DTC should be placed under thyroid hormone suppressive therapy after initial surgical therapy irrespective of whether they did or did not receive 131I. The goal of thyroid hormone suppressive therapy is to achieve a TSH level below the normal range, typically 12 months in order to ensure maximum benefit from each treatment, defined by the TG nadir, and to establish the presence of progressive disease. Deliberate transition of care from a pediatric to an adult multidisciplinary team is essential due to the risk of recurrent disease and the requirement for life-long surveillance.

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Andrew J. Bauer, MD, FAAP Thyroid Center, Division of Endocrinology and Diabetes, Children’s Hospital of Philadelphia 34th Street and Civic Center Boulevard, Suite 11NW30 Philadelphia, PA 19104-4399 (USA) E-Mail [email protected]


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Incidental thyroid nodules and thyroid cancer: considerations before determining management.

Thyroid nodules and evaluation of thyroid cancer risk.

Lymphoscintigraphy in Differentiated Thyroid Cancer.

Thyroglobulin in differentiated thyroid cancer.

Inaugural Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer: Children Are Not Small Adults.

Differentiated Thyroid Cancer in Children: Prevalence and Predictors in a Large Cohort with Thyroid Nodules Followed Prospectively.

Obesity Does Not Modify the Risk of Differentiated Thyroid Cancer in a Cytological Series of Thyroid Nodules.

Thyroid gland: Iodine deficiency and thyroid nodules.

Neoadjuvant Therapy in Differentiated Thyroid Cancer.

Parasitic thyroid nodules: cancer or not?

[Advanced radioiodine-refractory differentiated thyroid cancer].

[Association of hyperthyroidism with differentiated thyroid cancer].

Management of Invasive Differentiated Thyroid Cancer.

Serum thyroglobulin in differentiated thyroid cancer.

Survival discriminants for differentiated thyroid cancer.

The Surgical Approach to Differentiated Thyroid Cancer.

Role of hemithyroidectomy in differentiated thyroid cancer.

Targeted therapies in advanced differentiated thyroid cancer.

Lymph Node Dissection for Differentiated Thyroid Cancer.

Update on differentiated thyroid cancer staging.

Differentiated thyroid carcinoma in lingual thyroid.

Diagnosing thyroid nodules.

Cystic thyroid nodules.

Thyroid nodules in pregnancy.