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Thyroid surgery in children
Seminars in Pediatric Surgery 23 (2014) 60–65
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Seminars in Pediatric Surgery journal homepage: www.elsevier.com/locate/sempedsurg
Thyroid surgery in children Daniel J. Ledbetter, MD, FACS, FAAPa,b,n a b
Department of Surgery, University of Washington, Seattle, Washington Seattle Children's Hospital, Sand Point Way, Seattle, Washington 98105
a r t i c l e in f o
Keywords: Thyroid Goiter Thyroid hormone Recurrent laryngeal nerve Thyroidectomy
abstract Although surgical conditions of the thyroid gland are uncommon in children, the increased incidence of thyroid cancer, combined with the fact that children's hospitals are increasingly treating older adolescents, means that it is important that all pediatric surgeons have a knowledge of these conditions. Abnormalities of the thyroid can be associated with abnormalities of thyroid function (hyperthyroidism or hypothyroidism) and/or can be associated with symmetrical or asymmetrical enlargement of the gland. & 2014 Elsevier Inc. All rights reserved.
Introduction Thyroid surgery in children is uncommon, but it is an increasingly important issue for pediatric surgeons as the incidence of thyroid cancer rises, and children's hospitals strive to provide comprehensive care for older adolescents. Surgical diseases of the thyroid are much more common in adults than in children and the evaluation and management of these conditions in children is largely extrapolated from the adult experience. This review of thyroid surgery in children begins with a brief examination of thyroid embryology, anatomy, and pathophysiology and then considers the evaluation and management of hyperthyroidism, an enlarged thyroid, thyroid nodules, and thyroid cancer in pediatric patients.
Thyroid embryology and anatomy The thyroid gland originates as a diverticulum of the endoderm of the embryonic pharynx at what will be recognized in postnatal life as the foramen cecum at the junction of the anterior twothirds and posterior one-third of the tongue. By day 24 of gestation, the thyroid diverticulum begins to migrate caudally. It passes through or nearby the hyoid bone, and by day 50 of gestation, the thyroid reaches its final position in the lower neck as two lobes, one on each side of the trachea, linked by a thin isthmus.1 Normally, the thyroid diverticulum involutes but a common variation of the gross anatomy of the thyroid gland is a n Correspondence address: Seattle Children's Hospital, Sand Point Way, Seattle, WA 98105. E-mail address: [email protected]
http://dx.doi.org/10.1053/j.sempedsurg.2014.03.002 1055-8586/& 2014 Elsevier Inc. All rights reserved.
pyramidal lobe that extends upward from the isthmus towards the hyoid bone.2 More proximal persistent remnants of the thyroid diverticulum may result in a thyroglossal duct cyst or sinus. Thyroglossal duct cysts are usually located in or near the midline between the hyoid bone and thyroid gland and are usually evident during childhood. They may be asymptomatic but are excised because of the risk of developing infection.3 Malignant transformation is a rare complication.4 Surgical excision of the thyroglossal duct cyst and the entire migration path of the thyroid diverticulum including the middle third of the hyoid bone is necessary to minimize the risk of recurrence.3–5 The thyroid gland has a rich blood supply from the superior and inferior thyroid arteries. The superior thyroid artery usually originates from the external carotid artery. It divides into anterior and posterior branches, which supply the upper pole of the thyroid. The inferior thyroid artery originates from the thyrocervical trunk and divides into an inferior branch that supplies the lower pole of the thyroid and a superior branch that helps supply the upper pole of the thyroid. Venous drainage of the thyroid is through vessels that accompany the arterial branches and in over half of patients through a large middle thyroid vein that leaves the mid-lateral thyroid and extends across the carotid artery before entering the internal jugular vein.2 Knowledge of the anatomy of adjacent recurrent laryngeal and superior laryngeal nerves is critical to minimize the risk of nerve injury during thyroid surgery.6 The recurrent laryngeal nerve is a branch of the vagus nerve and is important for vocal cord movement. The path of the recurrent laryngeal nerve from the vagus to the larynx is the result of its relationship with the developing aortic arches. On the left, the recurrent nerve passes around the sixth arch that descends and becomes the ductus arteriosus in utero and the ligamentum artersiosum after birth. After looping
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around the ligamentum arteriosum and aortic arch, it ascends in the tracheoesophageal groove in a nearly vertical direction. On the right, the fifth and sixth arches involute and the recurrent laryngeal nerve loops around the fourth arch, which becomes the right subclavian artery. This results in the right recurrent laryngeal nerve ascending more obliquely to the larynx. When the fourth aortic arch involutes then the right subclavian artery is aberrant with its origin from the aortic arch distal to the normal origin of the left subclavian artery. In this circumstance, the right “recurrent” laryngeal nerve is nonrecurrent and comes directly from the vagus nerve into the side of the larynx. The course of the recurrent laryngeal nerve near the thyroid gland is variable and it may lay anterior or posterior to the inferior thyroid artery or within its branches. The nerve may bifurcate before entering the larynx. In bifurcated nerves, the motor fibers are usually in the anterior/medial branch and the sensory fibers are in the posterior/ lateral branch.7,8 It is critical to preserve both branches. The recurrent laryngeal nerve is closest to the thyroid and most vulnerable to surgical injury at the ligament of Berry, the tough connective tissue that binds the thyroid gland to the trachea.2 The superior laryngeal nerve is a much smaller branch of the vagus that splits into an internal branch that goes through the thyrohyoid membrane to provide sensation to the larynx proximal to the vocal cords and an external branch that innervates the cricothyroid muscle. The cricothyroid muscle plays a major role in voice strength and quality, so it is important to avoid injury to this nerve during thyroid surgery. The external branch of the superior laryngeal nerve has a variable relationship with branches of the superior thyroid artery before entering the cricothyroid muscle, so it is safest to ligate individual branches of the superior thyroid artery as they enter the gland.9 Histologically, the thyroid is made up of spherical follicles that consist of a single layer of thyroid epithelial cells (follicular cells) surrounding a follicular lumen containing colloid. The follicular cells produce thyroid hormone. The other hormonally active cells in the thyroid gland are parafollicular C cells that produce calcitonin. Parafollicular C cells are neuroendocrine cells that originate from the ultimobranchial bodies of the embryonic pharynx and migrate to join the thyroid during its midline descent into the neck. As their name suggests, parafollicular C cells are scattered between the follicles.
Thyroid physiology The function of the thyroid gland is to produce the thyroid hormones thyroxine (T4) and triiodothyronine (T3) and release them to the systemic circulation in a controlled manner. T3 is the active hormone that interacts with receptors in the nuclei of almost every cell in the body to regulate metabolism. Thyroid hormones also sensitize tissues to catecholamine stimulation and are critical to normal neurologic development. Thyroid hormone secretion is controlled by thyrotropin, also known as thyroidstimulating hormone (TSH), from the anterior pituitary, which in turn is controlled by thyrotropin-releasing hormone (TRH) from the hypothalamus. TSH stimulates specific receptors on thyroid follicular cells to increase thyroid hormone production. Thyroid hormone synthesis is dependent upon dietary intake of iodine and the follicular cells' ability to concentrate iodine. Once inside the follicular cells, iodine is transported into the colloid of the follicular lumen where it binds with tyrosine residues of thyroglobulin, a large glycoprotein synthesized by follicular cells. The iodinated tyrosine residues within thyroglobulin are conjugated to form thyroid hormones. Thyroglobulin that contains T3 and T4 is taken back into the follicular cell by endocytosis. In the follicular cell, the
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thyroglobulin undergoes proteolysis and the thyroid hormones T3 and T4 are released into the systemic circulation. More than 99% of circulating T3 and T4 is protein bound. The bound form is protected from cellular uptake and metabolism. Only the free forms enter cells and exert their biologic effects. Calcitonin is a 32 amino acid peptide produced by parafollicular C cells in response to rising calcium levels. Calcitonin does not seem to play a role in human calcium homeostasis and high levels have no adverse effects. Calcitonin is a tumor marker for the C cell malignancy medullary thyroid cancer.
Thyroid enlargement An abnormally enlarged thyroid gland is known as a goiter. The term “goiter” is associated with a variety of anatomic and pathologic conditions and may be seen in patients who are hyperthyroid, hypothyroid, or euthyroid. In many parts of the world, dietary insufficiency of iodine is still common and the resulting constant stimulation of the thyroid by TSH leads to a thyroid enlargement known as endemic goiter. In the developed world, iodine insufficiency is uncommon and goiters are more typically due to inflammatory conditions or nodular changes in the thyroid. Thyroid enlargement is often asymptomatic but when thyroid enlargement produces symptoms due to compression of the underlying trachea or other mass effects then surgical resection is indicated.
Hyperthyroidism A hyperfunctioning thyroid produces elevated levels of thyroid hormones or hyperthyroidism and the clinical condition of thyrotoxicosis. The clinical manifestations of hyperthyroidism in children include weight loss, fatigue, changes in behavior, heat intolerance, tremor, and goiter.10 In children and adults, the most common cause of hyperthyroidism is Graves disease, which results from autoimmune stimulation of the TSH receptor on follicular cells with resulting unregulated secretion of thyroid hormones. Graves disease may be treated with antithyroid drugs, radioactive iodine, or thyroidectomy. The treatment chosen reflects patient, family, and physician preferences and choice of which risks to take since each treatment has advantages and disadvantages. Antithyroid drugs are often the first line of treatment. They are effective but they have potential serious side effects. In addition, lasting, spontaneous remission occurs in less than 25% of children.11 These disadvantages lead many patients to have definitive treatment to ablate thyroid follicular cells with radioactive iodine or thyroidectomy. Complete ablation creates permanent hypothyroidism, which requires lifelong thyroid hormone replacement. Treatment with radioactive iodine avoids the risks of surgery while surgery prevents the risks of radiation exposure. Concerns about radiation exposure make surgery the definitive treatment of choice in patients less than 5 years of age.12 Surgery is also the recommended definitive treatment when the thyroid is large, especially if there are signs of airway compression, since large glands are unlikely to be ablated by radioactive iodine.13 Less common causes of the hyperthyroidism that could require surgery include toxic multinodular goiter and a solitary, hyperfunctioning thyroid nodule. Toxic multinodular goiter is diagnosed when a patient with hyperthyroidism has an enlarged thyroid with multiple, hyperfunctioning nodules (either palpable or detected only by ultrasound).14 The diagnosis is confirmed by thyroid scanning that shows increased uptake in multiple nodules. Surgery is often recommended as definitive treatment because high doses and multiple courses of radioactive iodine are often required to
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ablate the enlarged gland. A solitary, hyperfunctioning adenoma or “toxic adenoma” is diagnosed when a patient has hyperthyroidism and a single nodule by ultrasound that has increased uptake on thyroid scan. Patients having surgical treatment for overt hyperthyroidism should be made euthyroid with antithyroid drugs preoperatively to reduce the risk of perioperative “thyroid storm.”15 Patients unable to tolerate antithyroid drugs or who are symptomatic despite with ongoing treatment with antithyroid drugs may be prepared for surgery with beta-blockers. In addition, patients with Graves disease who are treated with inorganic iodine for 7–10 days before surgery will rapidly (although transiently) decrease thyroid hormone secretion and thyroid gland vascularity.12 Patients with toxic nodular goiter and solitary hyperfunctioning nodules should not receive inorganic iodine as it may exacerbate thyrotoxicosis. The recommended surgical treatment for hyperthyroidism caused by Graves disease and toxic multinodular goiter is a total or near-total thyroidectomy because the operative risks of total thyroidectomy and subtotal thyroidectomy are similar and total thyroidectomy minimizes the risk of recurrent hyperthyroidism and the subsequent need for further surgery or radiation.12,16 For a solitary toxic nodule, surgical resection of the adenoma with lobectomy and isthmusectomy is the usual definitive treatment if the remaining thyroid is normal.
Thyroid nodules Thyroid nodules are common in adults in the United States. They are much more common in women than in men and their prevalence increases with age. Roughly 5% of adults will have palpable nodularity of their thyroid.17 Thyroid nodules are much more commonly detected by ultrasound18 and do not necessarily correlate with the physical examination findings of nodularity.19
The power of ultrasound to identify small, impalpable thyroid nodules has made it the gold standard for diagnosis. Although less common than in adults, thyroid nodules are not rare in children. During a large screening effort to detect thyroid abnormalities in children with possible radiation exposure in the American Southwest, almost 2% of school-aged children were found to have palpable thyroid nodularity.20 A thyroid nodule in an adult or a child may be a manifestation of inflammatory thyroid disease or represent a cyst, benign tumor (usually follicular adenoma), or malignant tumor. The risk of malignancy is the primary reason to evaluate thyroid nodules. In adults, the risk of a thyroid nodule being malignant is 5–15%, depending upon the patient's age, sex, family history, history of radiation exposure, and other risk factors.21 The risk of a thyroid nodule in a child being malignant is probably equal to or higher than the risk in adults.22–24 Several groups including American Thyroid Association (ATA) and National Comprehensive Cancer Network (NCCN) have established clinical practice guidelines addressing the evaluation and management of thyroid nodules and thyroid cancer.25 Although these guidelines mainly concern adults, they also typically make recommendations for children and adolescents. Specifically the ATA recommends that the evaluation and management of thyroid nodules should be the same for children and adults.17 A brief algorithm for the evaluation of thyroid nodules in children is outlined in the Figure, and further explanation of the guiding principles follows below. The main purpose of the initial evaluation is to identify thyroid nodules that should be biopsied either by fine-needle aspiration (FNA) or excision (typically lobectomy and isthmusectomy). Thyroid nodules that are not palpable but only found incidentally on an imaging studies seem to have a similar risk of malignancy as palpable nodules and so should be managed similarly.17
Fig. Evaluation of a thyroid nodule.
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The evaluation of a thyroid nodule begins with a history and physical examination. The basic medical history should be supplemented by a specific assessment of the patient and family's awareness of any neck lump including its onset and growth rate. Systemic symptoms of hyperthyroidism and hypothyroidism and associated symptoms such as neck pain, hoarseness, and change in voice quality should be identified. It is also critical to determine if there has been a history of radiation exposure—either head and neck irradiation, total body irradiation for bone marrow transplantation, or radiation fallout, as children exposed to ionizing radiation have an increased risk of developing thyroid nodules and thyroid cancer.26,27 In addition, family history of autoimmune disease, thyroid cancer, or syndromes with a risk of thyroid cancer should be sought. Syndromes with a risk of thyroid cancer include multiple endocrine neoplasia type 2 (MEN2), familial medullary thyroid cancer (MTC), Gardner's syndrome, and Cowden's syndrome. MEN2 and familial MTC are both caused by mutations in the RET proto-oncogene and are inherited in an autosomal dominant pattern. Essentially all patients with MEN2 will suffer from MTC although the age of onset of the disease is variable and seems to be related to the specific mutation.28 Patients with MEN2 usually present with the MTC and only rarely present with pheochromocytoma and even more rarely present with hyperparathyroidism.29 Gardner's syndrome is a subset of familial adenomatous polyposis that is notable for characteristic benign extraintestinal lesions, such as osteomas and epidermal inclusion cysts, and an increased risk for extracolonic malignancies, including thyroid cancer.30 Cowden's syndrome is the best known of several rare syndromes associated with mutations in the phosphatase and tensin homolog (PTEN) gene. It is notable for macrocephaly, multiple hamartomas, and distinctive benign facial lesions (trichilemmomas, acral keratoses, and facial papules), and an increased risk of thyroid, breast, and kidney cancer. The thyroid cancers are primarily papillary but occasionally follicular and they may present at a young age.31 Patients with Cowden's syndrome are also at an increased risk for benign palpable thyroid nodularity.32 Patients with a suspected thyroid nodule require a general physical examination including evaluation for signs of hypothyroidism and hyperthyroidism, assessment of the size, character, consistency, and mobility of the thyroid nodule, and identification of associated cervical lymphadenopathy. After the history and physical examination, the evaluation continues with determination of TSH and a neck ultrasound. The neck ultrasound confirms the presence of a thyroid nodule, determines its size and character, and identifies other thyroid nodules. If a thyroid nodule is confirmed by ultrasound, then the rest of the neck is evaluated for abnormal lymph nodes suggesting metastases. If a thyroid nodule is not seen, then other areas of the neck can be investigated as the source of the palpable abnormality. The ATA recommends that after history and physical examination, the next investigation should be the determination of TSH.17 If the TSH is low, then the next step would be a radionuclide thyroid scan. If the thyroid scan shows a hyperfunctioning nodule, then the patient should be evaluated for hyperthyroidism, and as noted above, might eventually require surgical resection for treatment of hyperthyroidism. An isolated hyperfunctioning nodule has a very low risk of malignancy and FNA is rarely indicated. If the TSH is normal or high, then evaluation would continue with the ultrasound. Patients with thyroid nodules and a high TSH have an increased risk of malignancy.33 Calcitonin testing for patients with thyroid nodules is controversial. An elevated calcitonin suggests medullary thyroid cancer but the yield is low. It is not recommended by most guidelines but there is a suggestion that calcitonin testing would be cost-effective in the United States.34 After history, physical examination, TSH, and cervical ultrasound, the next decision is whether or not a thyroid nodule needs
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to be biopsied. Typically, the decision depends upon the size of the nodule, ultrasound features of the nodule, and other clinical risk factors. Solid nodules greater than 1.0 cm in diameter should usually be biopsied; however, biopsy may be warranted in smaller nodules in patients with high-risk clinical features. Ultrasound features of nodules that increase the risk of malignancy include microcalcifications, hypoechogenicity, increased vascularity within the nodule, irregular nodule margins, and disruption of the thyroid capsule.35,36 Ultrasound findings that decrease the chance of malignancy include simple cysts (malignancy is rare and biopsy for diagnosis is not indicated) and spongiform appearance. Highrisk clinical features include history of radiation exposure, history of a syndrome with increased thyroid cancer risk, family history of thyroid cancer in a first-degree relative, or a thyroid abnormality discovered to be FDG avid on PET scanning.17,37 Fine-needle aspiration (FNA) can usually be performed in cooperative patients with only local anesthesia; however, some children require sedation or even general anesthesia. The need for general anesthesia makes decision-making more complex. Performing FNA under ultrasound guidance is recommended to increase the yield of adequate biopsies and is especially useful when the nodules are small or when previous biopsies have been nondiagnostic.17 FNA results may be classified as nondiagnostic, benign, follicular or Hürthle cell neoplasm, follicular lesion of undetermined significance, or definite or suspicious for malignancy.17,38 If the FNA is nondiagnostic because of insufficient biopsy material then the patient may be followed and the FNA repeated under ultrasound guidance. When FNA is repeatedly nondiagnostic, patients require close follow-up with ultrasound and thyroid lobectomy and isthmusectomy are considered for definitive diagnosis. If the biopsy is benign then the patient can be followed up by physical examination and ultrasound. There is a small risk of false-negative FNA, so if the lesion enlarges, then the FNA may be repeated or surgical resection considered. FNA showing an indeterminate cytology of either follicular neoplasm or Hürthle cell neoplasm and FNA showing atypia or a follicular lesion of undetermined significance are traditional reasons for lobectomy and isthmusectomy because of a 5–10% risk of malignancy for a follicular lesion of undetermined significance and 20–30% risk of malignancy for follicular or Hürthle cell neoplasms. Surgical resection was necessary because the histologic determination of follicular or Hürthle cell malignancy depends upon finding vascular or capsular invasion, which requires examination of the entire lesion. There is some suggestion that Hürthle cell changes alone may not require surgical resection,39 and there is hope that molecular diagnostic markers may define the patients in these indeterminate groups who are at higher risk of malignancy and allow low-risk patients to avoid surgery.17 When the FNA shows thyroid cancer or is suspicious for cancer, then the patient should undergo primary surgical treatment as discussed below.
Thyroid cancer The incidence of thyroid cancer is increasing in adults and children, and there were an estimated 60,000 new cases in the United States in 2013.40 The overwhelming majority of cases are adults but incidence rate begins to rise in adolescence and it is one of the most frequent solid tumors of adolescents and young adults.41 When only children and adolescents are considered, there are an estimated 300–400 cases per year making thyroid cancer one of the more common solid tumors of childhood. The pathology of thyroid cancer is similar in adults and children. Of 1753 thyroid cancers in children reported to the SEER database,
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83% were papillary thyroid cancer, 10% were follicular thyroid cancer, 5% medullary thyroid cancer (MTC), and 2% were “other” types of thyroid cancer.42 As in adults, the primary treatment of thyroid cancer in children is surgery. The major questions of surgical treatment are the following: (1) How much thyroid needs to be removed? (2) Is regional lymph node resection required, and if so, how extensive does this need to be?43 As for adults, it is useful to consider papillary and follicular thyroid cancers together as “differentiated” thyroid cancers since their evaluation and management are very similar. MTC is very different and will be considered separately. When MTC is discovered on biopsy, then preoperative evaluation is done to stage the disease and assess for associated abnormalities. The extent of the disease is evaluated with ultrasound of the central and lateral neck to assess for lymphadenopathy. Calcitonin and carcinoembryonic antigen (CEA) serve as valuable tumor markers so their levels are checked. An in-depth family history, RET mutation evaluation, screening for pheochromocytoma, and serum calcium determination are done to assess for familial MTC and MEN2. The primary surgical treatment of MTC is a total thyroidectomy with bilateral central (level VI) lymph node resection.28 More extended lymph node dissection is done if there is evidence of further lymph node involvement. The other common clinical scenario involving MTC in children is the asymptomatic patient who presents after screening evaluation shows a RET mutation that places them at risk for MTC. These patients require total thyroidectomy. The timing of their operation is guided by the specific mutation28 and how the family judges the risks of developing MTC versus the risks of the operation. The need for central node dissection is more debatable in the setting of prophylactic thyroidectomy in patients with RET mutations but no evidence of MTC. When differentiated thyroid cancer is found on FNA, then ultrasound evaluation of lymph nodes of the central and lateral neck is done. This evaluation is important since spread to lymph nodes is common and clinical evidence of gross disease in regional lymph nodes will drive the decision for lymph node dissection. Ultrasound detection of lymph node abnormalities in the central neck is more difficult because of the adjacent thyroid, spine, and trachea. The accuracy of ultrasound is dependent upon the skill and experience of the sonographer. FNA of suspicious lymph nodes may be performed to define metastatic disease and determine the need for lymph node resection. For adults and children with differentiated thyroid cancer, guidelines generally recommend total thyroidectomy for tumors larger than 1 cm or more in diameter, if the tumor extends beyond the capsule of the thyroid, if metastases are present, if multifocal disease suspected, or if the patient is at high risk for recurrence.17 This recommendation is supported by an analysis of 50,000 patients that showed that total thyroidectomy for tumors 4 1 cm resulted in fewer recurrences and improved survival.44 Total thyroidectomy is also the recommended operation for thyroid cancer in children and it is being increasingly utilized.45 Central and lateral neck dissection is recommended for patients with any involved lymph nodes to improve local and regional control. Prophylactic lymph node dissection is debatable46 and is not generally recommended for children at this time. When differentiated thyroid cancer is discovered on the pathological examination of partial thyroid resections, then completion thyroidectomy is recommended.17 However, some argue that lobectomy and isthmusectomy followed by radioiodine ablation of remaining thyroid tissue and suppression of TSH with thyroid hormone replacement leads to excellent long-term survival.47 The ideal adjuvant treatment for children with thyroid cancer following primary surgery is unclear. Postoperative treatment with radioactive iodine is based on upon the size of the original tumor,
the completeness of surgical excision, and presence of metastases.48 Radioactive iodine is used after surgery to image for metastatic disease, to treat residual tumor and metastases, and to ablate any remaining normal thyroid tissue to allow more accurate monitoring for recurrent disease.17 Radioactive iodine used for therapy (131-Iodine) kills cells by emitting beta radiation. The penetration of the radiation is only 1–2 mm, so the effectiveness of 131-Iodine depends upon its uptake and concentration by the target cells. This is why 131-Iodine is effective against differentiated thyroid cancers but not against the malignant neuroendocrine cells of MTC. The uptake of iodine and radioactive iodine depends upon TSH stimulation and relative iodine insufficiency. This is the reason that patients require special preparation with limited dietary intake of iodine and sometimes stimulation with TSH before studies and treatment with radioactive iodine. The need for a target cell to actively concentrate iodine is the reason why it is important to avoid large doses of iodinated contrast agents that are typically given with CT scans with intravenous contrast. The excess iodine saturates thyroid tissue and complicates postoperative radioiodine diagnostic scanning and may delay treatment with therapeutic radioiodine for weeks to months.48 The outlook for children with thyroid cancer is remarkably favorable, even more favorable than adults with the disease. Even though children tend to present with more advanced disease, they typically respond well to treatment. In a review of 540 children from nine centers, the recurrence rate was 10–35% but only 13 of the 540 patients died of their disease 12–33 years after their operation.49 The largest group of patients analyzed were 1753 children in the SEER database report mentioned previously; 93% of the group had differentiated thyroid cancers and their postoperative survivals at 5, 15, and 30 years were all greater than 90%.42
Conclusions Although, in general, thyroid problems needing operative intervention are much more frequent in adults, thyroid surgery is an important part of the comprehensive care of children and adolescents. For thyroid nodules and thyroid cancers, the low numbers of pediatric cases, high cure rates, prolonged survival of patients with persistent or recurrent disease, changing patterns of staging, and lack of randomized, controlled trials make definitive recommendations for individual children difficult. However, despite these challenges it seems that, for the most part, the guidelines for care of adults can be extrapolated to children and their thyroid nodules can be effectively evaluated with ultrasound and FNA. In addition, treatment of children with thyroid cancer by total thyroidectomy, central and lateral lymph node dissection for those with clinical or imaging evidence of node involvement, and postoperative radioiodine is extremely successful. The ideal process to provide the best possible outcomes for children with surgical thyroid diseases requires a team of physicians and surgeons who have expertise and experience in the care of children and who can successfully collaborate with adult specialists to provide high-quality, cutting-edge care in a setting that has the optimal resources to care for children and adolescents. References 1. Fancy T, Gallagher D 3rd, Hornig JD. Surgical anatomy of the thyroid and parathyroid glands. Otolaryngol Clin North Am. 2010;43(2):221–227. 2. Miller BS, Gauger PG. Thyroid gland. In: Mulholland M, Lillemoe K, Doherty G, Maier R, Simeone D, Upchurch G, editors. Greenfield's Surgery. 5th ed, Philadelphia: Lippincott Williams & Wilkins; 2011. p. 1282–1302. 3. Organ GM, Organ CH Jr. Thyroid gland and surgery of the thyroglossal duct: exercise in applied embryology. World J Surg. 2000;24(8):886–890. 4. Ellis PD, van Nostrand AW. The applied anatomy of thyroglossal tract remnants. Laryngoscope. 1977;87(5 Pt 1):765–770.
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5. Sistrunk WE. The surgical treatment of cysts of the thyroglossal tract. Ann Surg. 1920;71(2):121–122. 6. Mohebati A, Shaha AR. Anatomy of thyroid and parathyroid glands and neurovascular relations. Clin Anat. 2012;25(1):19–31. 7. Serpell JW, Yeung MJ, Grodski S. The motor fibers of the recurrent laryngeal nerve are located in the anterior extralaryngeal branch. Ann Surg. 2009; 249(4):648–652. 8. Kandil E, Abdelghani S, Friedlander P, et al. Motor and sensory branching of the recurrent laryngeal nerve in thyroid surgery. Surgery. 2011;150(6):1222–1227. 9. Bliss RD, Gauger PG, Delbridge LW. Surgeon's approach to the thyroid gland: surgical anatomy and the importance of technique. World J Surg. 2000; 24(8):891–897. 10. Williamson S, Greene SA. Incidence of thyrotoxicosis in childhood: a national population based study in the UK and Ireland. Clin Endocrinol. 2010;72(3): 358–363. 11. Rivkees SA. The management of hyperthyroidism in children with emphasis on the use of radioactive iodine. Pediatr Endocrinol Rev. 2003;1(suppl 2):212–221. 12. Bahn RS, Burch HB, Cooper DS, et al. Hyperthyroidism and other causes of thyrotoxicosis: management guidelines of the American Thyroid Association and American Association of Clinical Endocrinologists. Thyroid. 2011;21(6): 593–646. 13. Peters H, Fischer C, Bogner U, Reiners C, Schleusener H. Treatment of Graves' hyperthyroidism with radioiodine: results of a prospective randomized study. Thyroid. 1997;7(2):247–251. 14. Williams JL, Paul D, Bisset G 3rd. Thyroid disease in children: part 2 : state-of-theart imaging in pediatric hyperthyroidism. Pediatr Radiol. 2013;43(10):1254–1264. 15. Burch HB, Wartofsky L. Life-threatening thyrotoxicosis. Thyroid storm. Endocrinol Metab Clin North Am. 1993;22(2):263–277. 16. Breuer CK, Solomon D, Donovan P, Rivkees SA, Udelsman R. Effect of patient age on surgical outcomes for Graves' disease: a case–control study of 100 consecutive patients at a high volume thyroid surgical center. Int J of Pediatr Endocrinol. 2013;2013(1):1. 17. Cooper DS, Doherty GM, Haugen BR, et al. Revised American Thyroid Association management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2009;19(11):1167–1214. 18. Ezzat S, Sarti DA, Cain DR, Braunstein GD. Thyroid incidentalomas: prevalence by palpation and ultrasonography. Arch Intern Med. 1994;154(16):1838–1840. 19. Marqusee E, Benson CB, Frates MC, et al. Usefulness of ultrasonography in the management of nodular thyroid disease. Ann Intern Med. 2000;133(9):696–700. 20. Rallison ML, Dobyns BM, Keating FR Jr., Rall JE, Tyler FH. Thyroid nodularity in children. J Am Med Assoc. 1975;233(10):1069–1072. 21. Hegedus L. Clinical practice. The thyroid nodule. N Engl J Med. 2004;351 (17):1764–1771. 22. Raab SS, Silverman JF, Elsheikh TM, Thomas PA, Wakely PE. Pediatric thyroid nodules: disease demographics and clinical management as determined by fine needle aspiration biopsy. Pediatrics. 1995;95(1):46–49. 23. Corrias A, Einaudi S, Chiorboli E, et al. Accuracy of fine needle aspiration biopsy of thyroid nodules in detecting malignancy in childhood: comparison with conventional clinical, laboratory, and imaging approaches. J Clin Endocrinol Metab. 2001;86(10):4644–4648. 24. Hung W. Solitary thyroid nodules in 93 children and adolescents: a 35-years experience. Horm Res. 1999;52(1):15–18. 25. McLeod DS, Sawka AM, Cooper DS. Controversies in primary treatment of lowrisk papillary thyroid cancer. Lancet. 2013;381(9871):1046–1057. 26. Taylor AJ, Croft AP, Palace AM, et al. Risk of thyroid cancer in survivors of childhood cancer: results from the British Childhood Cancer Survivor Study. Int J Cancer. 2009;125(10):2400–2405. 27. Pacini F, Vorontsova T, Demidchik EP, et al. Post-Chernobyl thyroid carcinoma in Belarus children and adolescents: comparison with naturally occurring thyroid carcinoma in Italy and France. J Clin Endocrinol Metab. 1997;82(11): 3563–3569.
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28. Kloos RT, Eng C, Evans DB, et al. Medullary thyroid cancer: management guidelines of the American Thyroid Association. Thyroid. 2009;19(6):565–612. 29. Machens A, Lorenz K, Dralle H. Peak incidence of pheochromocytoma and primary hyperparathyroidism in multiple endocrine neoplasia 2: need for age-adjusted biochemical screening. J Clin Endocrinol Metab. 2013;98(2): E336–E345. 30. Herraiz M, Barbesino G, Faquin W, et al. Prevalence of thyroid cancer in familial adenomatous polyposis syndrome and the role of screening ultrasound examinations. Clin Gastroenterol Hepatol. 2007;5(3):367–373. 31. Smith JR, Marqusee E, Webb S, et al. Thyroid nodules and cancer in children with PTEN hamartoma tumor syndrome. J Clin Endocrinol Metab. 2011;96(1): 34–37. 32. Hall JE, Abdollahian DJ, Sinard RJ. Thyroid disease associated with Cowden syndrome: a meta-analysis. Head Neck. 2013;35(8):1189–1194. 33. Boelaert K, Horacek J, Holder RL, Watkinson JC, Sheppard MC, Franklyn JA. Serum thyrotropin concentration as a novel predictor of malignancy in thyroid nodules investigated by fine-needle aspiration. J Clin Endocrinol Metab. 2006; 91(11):4295–4301. 34. Cheung K, Roman SA, Wang TS, Walker HD, Sosa JA. Calcitonin measurement in the evaluation of thyroid nodules in the United States: a cost-effectiveness and decision analysis. J Clin Endocrinol Metab. 2008;93(6):2173–2180. 35. Cappelli C, Castellano M, Pirola I, et al. The predictive value of ultrasound findings in the management of thyroid nodules. QJM. 2007;100(1):29–35. 36. Horvath E, Majlis S, Rossi R, et al. An ultrasonogram reporting system for thyroid nodules stratifying cancer risk for clinical management. J Clin Endocrinol Metab. 2009;94(5):1748–1751. 37. Are C, Hsu JF, Ghossein RA, Schoder H, Shah JP, Shaha AR. Histological aggressiveness of fluorodeoxyglucose positron-emission tomogram (FDGPET)-detected incidental thyroid carcinomas. Ann Surg Oncol. 2007;14(11): 3210–3215. 38. Layfield LJ, Cibas ES, Gharib H, Mandel SJ. Thyroid aspiration cytology: current status. CA Cancer J Clin. 2009;59(2):99–110. 39. Hudak K, Mazeh H, Sippel RS, Chen H. Hurthle cell metaplasia on fine-needle aspiration biopsy is not by itself an indication for thyroid surgery. Am J Surg. 2012;203(3):287–290. 40. Siegel R, Naishadham D, Jemal A. Cancer statistics, 2013. CA Cancer J Clin. 2013;63(1):11–30. 41. Wu XC, Chen VW, Steele B, et al. Cancer incidence in adolescents and young adults in the United States, 1992-1997. J Adolesc Health. 2003;32(6):405–415. 42. Hogan AR, Zhuge Y, Perez EA, Koniaris LG, Lew JI, Sola JE. Pediatric thyroid carcinoma: incidence and outcomes in 1753 patients. J Surg Res. 2009; 156(1):167–172. 43. Hartl DM, Travagli JP. The updated American Thyroid Association Guidelines for management of thyroid nodules and differentiated thyroid cancer: a surgical perspective. Thyroid. 2009;19(11):1149–1151. 44. Bilimoria KY, Bentrem DJ, Ko CY, et al. Extent of surgery affects survival for papillary thyroid cancer. Ann Surg. 2007;246(3):375–381. 45. Raval MV, Bentrem DJ, Stewart AK, Ko CY, Reynolds M. Utilization of total thyroidectomy for differentiated thyroid cancer in children. Ann Surg Oncol. 2010;17(10):2545–2553. 46. Mazzaferri EL, Doherty GM, Steward DL. The pros and cons of prophylactic central compartment lymph node dissection for papillary thyroid carcinoma. Thyroid. 2009;19(7):683–689. 47. Randolph GW, Daniels GH. Radioactive iodine lobe ablation as an alternative to completion thyroidectomy for follicular carcinoma of the thyroid. Thyroid. 2002;12(11):989–996. 48. Parisi MT, Mankoff D. Differentiated pediatric thyroid cancer: correlates with adult disease, controversies in treatment. Semin Nucl Med. 2007;37(5): 340–356. 49. Feinmesser R, Lubin E, Segal K, Noyek A. Carcinoma of the thyroid in children— a review. J Pediatr Endocrinol Metab. 1997;10(6):561–568.
Contents lists available at ScienceDirect
Seminars in Pediatric Surgery journal homepage: www.elsevier.com/locate/sempedsurg
Thyroid surgery in children Daniel J. Ledbetter, MD, FACS, FAAPa,b,n a b
Department of Surgery, University of Washington, Seattle, Washington Seattle Children's Hospital, Sand Point Way, Seattle, Washington 98105
a r t i c l e in f o
Keywords: Thyroid Goiter Thyroid hormone Recurrent laryngeal nerve Thyroidectomy
abstract Although surgical conditions of the thyroid gland are uncommon in children, the increased incidence of thyroid cancer, combined with the fact that children's hospitals are increasingly treating older adolescents, means that it is important that all pediatric surgeons have a knowledge of these conditions. Abnormalities of the thyroid can be associated with abnormalities of thyroid function (hyperthyroidism or hypothyroidism) and/or can be associated with symmetrical or asymmetrical enlargement of the gland. & 2014 Elsevier Inc. All rights reserved.
Introduction Thyroid surgery in children is uncommon, but it is an increasingly important issue for pediatric surgeons as the incidence of thyroid cancer rises, and children's hospitals strive to provide comprehensive care for older adolescents. Surgical diseases of the thyroid are much more common in adults than in children and the evaluation and management of these conditions in children is largely extrapolated from the adult experience. This review of thyroid surgery in children begins with a brief examination of thyroid embryology, anatomy, and pathophysiology and then considers the evaluation and management of hyperthyroidism, an enlarged thyroid, thyroid nodules, and thyroid cancer in pediatric patients.
Thyroid embryology and anatomy The thyroid gland originates as a diverticulum of the endoderm of the embryonic pharynx at what will be recognized in postnatal life as the foramen cecum at the junction of the anterior twothirds and posterior one-third of the tongue. By day 24 of gestation, the thyroid diverticulum begins to migrate caudally. It passes through or nearby the hyoid bone, and by day 50 of gestation, the thyroid reaches its final position in the lower neck as two lobes, one on each side of the trachea, linked by a thin isthmus.1 Normally, the thyroid diverticulum involutes but a common variation of the gross anatomy of the thyroid gland is a n Correspondence address: Seattle Children's Hospital, Sand Point Way, Seattle, WA 98105. E-mail address: [email protected]
http://dx.doi.org/10.1053/j.sempedsurg.2014.03.002 1055-8586/& 2014 Elsevier Inc. All rights reserved.
pyramidal lobe that extends upward from the isthmus towards the hyoid bone.2 More proximal persistent remnants of the thyroid diverticulum may result in a thyroglossal duct cyst or sinus. Thyroglossal duct cysts are usually located in or near the midline between the hyoid bone and thyroid gland and are usually evident during childhood. They may be asymptomatic but are excised because of the risk of developing infection.3 Malignant transformation is a rare complication.4 Surgical excision of the thyroglossal duct cyst and the entire migration path of the thyroid diverticulum including the middle third of the hyoid bone is necessary to minimize the risk of recurrence.3–5 The thyroid gland has a rich blood supply from the superior and inferior thyroid arteries. The superior thyroid artery usually originates from the external carotid artery. It divides into anterior and posterior branches, which supply the upper pole of the thyroid. The inferior thyroid artery originates from the thyrocervical trunk and divides into an inferior branch that supplies the lower pole of the thyroid and a superior branch that helps supply the upper pole of the thyroid. Venous drainage of the thyroid is through vessels that accompany the arterial branches and in over half of patients through a large middle thyroid vein that leaves the mid-lateral thyroid and extends across the carotid artery before entering the internal jugular vein.2 Knowledge of the anatomy of adjacent recurrent laryngeal and superior laryngeal nerves is critical to minimize the risk of nerve injury during thyroid surgery.6 The recurrent laryngeal nerve is a branch of the vagus nerve and is important for vocal cord movement. The path of the recurrent laryngeal nerve from the vagus to the larynx is the result of its relationship with the developing aortic arches. On the left, the recurrent nerve passes around the sixth arch that descends and becomes the ductus arteriosus in utero and the ligamentum artersiosum after birth. After looping
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around the ligamentum arteriosum and aortic arch, it ascends in the tracheoesophageal groove in a nearly vertical direction. On the right, the fifth and sixth arches involute and the recurrent laryngeal nerve loops around the fourth arch, which becomes the right subclavian artery. This results in the right recurrent laryngeal nerve ascending more obliquely to the larynx. When the fourth aortic arch involutes then the right subclavian artery is aberrant with its origin from the aortic arch distal to the normal origin of the left subclavian artery. In this circumstance, the right “recurrent” laryngeal nerve is nonrecurrent and comes directly from the vagus nerve into the side of the larynx. The course of the recurrent laryngeal nerve near the thyroid gland is variable and it may lay anterior or posterior to the inferior thyroid artery or within its branches. The nerve may bifurcate before entering the larynx. In bifurcated nerves, the motor fibers are usually in the anterior/medial branch and the sensory fibers are in the posterior/ lateral branch.7,8 It is critical to preserve both branches. The recurrent laryngeal nerve is closest to the thyroid and most vulnerable to surgical injury at the ligament of Berry, the tough connective tissue that binds the thyroid gland to the trachea.2 The superior laryngeal nerve is a much smaller branch of the vagus that splits into an internal branch that goes through the thyrohyoid membrane to provide sensation to the larynx proximal to the vocal cords and an external branch that innervates the cricothyroid muscle. The cricothyroid muscle plays a major role in voice strength and quality, so it is important to avoid injury to this nerve during thyroid surgery. The external branch of the superior laryngeal nerve has a variable relationship with branches of the superior thyroid artery before entering the cricothyroid muscle, so it is safest to ligate individual branches of the superior thyroid artery as they enter the gland.9 Histologically, the thyroid is made up of spherical follicles that consist of a single layer of thyroid epithelial cells (follicular cells) surrounding a follicular lumen containing colloid. The follicular cells produce thyroid hormone. The other hormonally active cells in the thyroid gland are parafollicular C cells that produce calcitonin. Parafollicular C cells are neuroendocrine cells that originate from the ultimobranchial bodies of the embryonic pharynx and migrate to join the thyroid during its midline descent into the neck. As their name suggests, parafollicular C cells are scattered between the follicles.
Thyroid physiology The function of the thyroid gland is to produce the thyroid hormones thyroxine (T4) and triiodothyronine (T3) and release them to the systemic circulation in a controlled manner. T3 is the active hormone that interacts with receptors in the nuclei of almost every cell in the body to regulate metabolism. Thyroid hormones also sensitize tissues to catecholamine stimulation and are critical to normal neurologic development. Thyroid hormone secretion is controlled by thyrotropin, also known as thyroidstimulating hormone (TSH), from the anterior pituitary, which in turn is controlled by thyrotropin-releasing hormone (TRH) from the hypothalamus. TSH stimulates specific receptors on thyroid follicular cells to increase thyroid hormone production. Thyroid hormone synthesis is dependent upon dietary intake of iodine and the follicular cells' ability to concentrate iodine. Once inside the follicular cells, iodine is transported into the colloid of the follicular lumen where it binds with tyrosine residues of thyroglobulin, a large glycoprotein synthesized by follicular cells. The iodinated tyrosine residues within thyroglobulin are conjugated to form thyroid hormones. Thyroglobulin that contains T3 and T4 is taken back into the follicular cell by endocytosis. In the follicular cell, the
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thyroglobulin undergoes proteolysis and the thyroid hormones T3 and T4 are released into the systemic circulation. More than 99% of circulating T3 and T4 is protein bound. The bound form is protected from cellular uptake and metabolism. Only the free forms enter cells and exert their biologic effects. Calcitonin is a 32 amino acid peptide produced by parafollicular C cells in response to rising calcium levels. Calcitonin does not seem to play a role in human calcium homeostasis and high levels have no adverse effects. Calcitonin is a tumor marker for the C cell malignancy medullary thyroid cancer.
Thyroid enlargement An abnormally enlarged thyroid gland is known as a goiter. The term “goiter” is associated with a variety of anatomic and pathologic conditions and may be seen in patients who are hyperthyroid, hypothyroid, or euthyroid. In many parts of the world, dietary insufficiency of iodine is still common and the resulting constant stimulation of the thyroid by TSH leads to a thyroid enlargement known as endemic goiter. In the developed world, iodine insufficiency is uncommon and goiters are more typically due to inflammatory conditions or nodular changes in the thyroid. Thyroid enlargement is often asymptomatic but when thyroid enlargement produces symptoms due to compression of the underlying trachea or other mass effects then surgical resection is indicated.
Hyperthyroidism A hyperfunctioning thyroid produces elevated levels of thyroid hormones or hyperthyroidism and the clinical condition of thyrotoxicosis. The clinical manifestations of hyperthyroidism in children include weight loss, fatigue, changes in behavior, heat intolerance, tremor, and goiter.10 In children and adults, the most common cause of hyperthyroidism is Graves disease, which results from autoimmune stimulation of the TSH receptor on follicular cells with resulting unregulated secretion of thyroid hormones. Graves disease may be treated with antithyroid drugs, radioactive iodine, or thyroidectomy. The treatment chosen reflects patient, family, and physician preferences and choice of which risks to take since each treatment has advantages and disadvantages. Antithyroid drugs are often the first line of treatment. They are effective but they have potential serious side effects. In addition, lasting, spontaneous remission occurs in less than 25% of children.11 These disadvantages lead many patients to have definitive treatment to ablate thyroid follicular cells with radioactive iodine or thyroidectomy. Complete ablation creates permanent hypothyroidism, which requires lifelong thyroid hormone replacement. Treatment with radioactive iodine avoids the risks of surgery while surgery prevents the risks of radiation exposure. Concerns about radiation exposure make surgery the definitive treatment of choice in patients less than 5 years of age.12 Surgery is also the recommended definitive treatment when the thyroid is large, especially if there are signs of airway compression, since large glands are unlikely to be ablated by radioactive iodine.13 Less common causes of the hyperthyroidism that could require surgery include toxic multinodular goiter and a solitary, hyperfunctioning thyroid nodule. Toxic multinodular goiter is diagnosed when a patient with hyperthyroidism has an enlarged thyroid with multiple, hyperfunctioning nodules (either palpable or detected only by ultrasound).14 The diagnosis is confirmed by thyroid scanning that shows increased uptake in multiple nodules. Surgery is often recommended as definitive treatment because high doses and multiple courses of radioactive iodine are often required to
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ablate the enlarged gland. A solitary, hyperfunctioning adenoma or “toxic adenoma” is diagnosed when a patient has hyperthyroidism and a single nodule by ultrasound that has increased uptake on thyroid scan. Patients having surgical treatment for overt hyperthyroidism should be made euthyroid with antithyroid drugs preoperatively to reduce the risk of perioperative “thyroid storm.”15 Patients unable to tolerate antithyroid drugs or who are symptomatic despite with ongoing treatment with antithyroid drugs may be prepared for surgery with beta-blockers. In addition, patients with Graves disease who are treated with inorganic iodine for 7–10 days before surgery will rapidly (although transiently) decrease thyroid hormone secretion and thyroid gland vascularity.12 Patients with toxic nodular goiter and solitary hyperfunctioning nodules should not receive inorganic iodine as it may exacerbate thyrotoxicosis. The recommended surgical treatment for hyperthyroidism caused by Graves disease and toxic multinodular goiter is a total or near-total thyroidectomy because the operative risks of total thyroidectomy and subtotal thyroidectomy are similar and total thyroidectomy minimizes the risk of recurrent hyperthyroidism and the subsequent need for further surgery or radiation.12,16 For a solitary toxic nodule, surgical resection of the adenoma with lobectomy and isthmusectomy is the usual definitive treatment if the remaining thyroid is normal.
Thyroid nodules Thyroid nodules are common in adults in the United States. They are much more common in women than in men and their prevalence increases with age. Roughly 5% of adults will have palpable nodularity of their thyroid.17 Thyroid nodules are much more commonly detected by ultrasound18 and do not necessarily correlate with the physical examination findings of nodularity.19
The power of ultrasound to identify small, impalpable thyroid nodules has made it the gold standard for diagnosis. Although less common than in adults, thyroid nodules are not rare in children. During a large screening effort to detect thyroid abnormalities in children with possible radiation exposure in the American Southwest, almost 2% of school-aged children were found to have palpable thyroid nodularity.20 A thyroid nodule in an adult or a child may be a manifestation of inflammatory thyroid disease or represent a cyst, benign tumor (usually follicular adenoma), or malignant tumor. The risk of malignancy is the primary reason to evaluate thyroid nodules. In adults, the risk of a thyroid nodule being malignant is 5–15%, depending upon the patient's age, sex, family history, history of radiation exposure, and other risk factors.21 The risk of a thyroid nodule in a child being malignant is probably equal to or higher than the risk in adults.22–24 Several groups including American Thyroid Association (ATA) and National Comprehensive Cancer Network (NCCN) have established clinical practice guidelines addressing the evaluation and management of thyroid nodules and thyroid cancer.25 Although these guidelines mainly concern adults, they also typically make recommendations for children and adolescents. Specifically the ATA recommends that the evaluation and management of thyroid nodules should be the same for children and adults.17 A brief algorithm for the evaluation of thyroid nodules in children is outlined in the Figure, and further explanation of the guiding principles follows below. The main purpose of the initial evaluation is to identify thyroid nodules that should be biopsied either by fine-needle aspiration (FNA) or excision (typically lobectomy and isthmusectomy). Thyroid nodules that are not palpable but only found incidentally on an imaging studies seem to have a similar risk of malignancy as palpable nodules and so should be managed similarly.17
Fig. Evaluation of a thyroid nodule.
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The evaluation of a thyroid nodule begins with a history and physical examination. The basic medical history should be supplemented by a specific assessment of the patient and family's awareness of any neck lump including its onset and growth rate. Systemic symptoms of hyperthyroidism and hypothyroidism and associated symptoms such as neck pain, hoarseness, and change in voice quality should be identified. It is also critical to determine if there has been a history of radiation exposure—either head and neck irradiation, total body irradiation for bone marrow transplantation, or radiation fallout, as children exposed to ionizing radiation have an increased risk of developing thyroid nodules and thyroid cancer.26,27 In addition, family history of autoimmune disease, thyroid cancer, or syndromes with a risk of thyroid cancer should be sought. Syndromes with a risk of thyroid cancer include multiple endocrine neoplasia type 2 (MEN2), familial medullary thyroid cancer (MTC), Gardner's syndrome, and Cowden's syndrome. MEN2 and familial MTC are both caused by mutations in the RET proto-oncogene and are inherited in an autosomal dominant pattern. Essentially all patients with MEN2 will suffer from MTC although the age of onset of the disease is variable and seems to be related to the specific mutation.28 Patients with MEN2 usually present with the MTC and only rarely present with pheochromocytoma and even more rarely present with hyperparathyroidism.29 Gardner's syndrome is a subset of familial adenomatous polyposis that is notable for characteristic benign extraintestinal lesions, such as osteomas and epidermal inclusion cysts, and an increased risk for extracolonic malignancies, including thyroid cancer.30 Cowden's syndrome is the best known of several rare syndromes associated with mutations in the phosphatase and tensin homolog (PTEN) gene. It is notable for macrocephaly, multiple hamartomas, and distinctive benign facial lesions (trichilemmomas, acral keratoses, and facial papules), and an increased risk of thyroid, breast, and kidney cancer. The thyroid cancers are primarily papillary but occasionally follicular and they may present at a young age.31 Patients with Cowden's syndrome are also at an increased risk for benign palpable thyroid nodularity.32 Patients with a suspected thyroid nodule require a general physical examination including evaluation for signs of hypothyroidism and hyperthyroidism, assessment of the size, character, consistency, and mobility of the thyroid nodule, and identification of associated cervical lymphadenopathy. After the history and physical examination, the evaluation continues with determination of TSH and a neck ultrasound. The neck ultrasound confirms the presence of a thyroid nodule, determines its size and character, and identifies other thyroid nodules. If a thyroid nodule is confirmed by ultrasound, then the rest of the neck is evaluated for abnormal lymph nodes suggesting metastases. If a thyroid nodule is not seen, then other areas of the neck can be investigated as the source of the palpable abnormality. The ATA recommends that after history and physical examination, the next investigation should be the determination of TSH.17 If the TSH is low, then the next step would be a radionuclide thyroid scan. If the thyroid scan shows a hyperfunctioning nodule, then the patient should be evaluated for hyperthyroidism, and as noted above, might eventually require surgical resection for treatment of hyperthyroidism. An isolated hyperfunctioning nodule has a very low risk of malignancy and FNA is rarely indicated. If the TSH is normal or high, then evaluation would continue with the ultrasound. Patients with thyroid nodules and a high TSH have an increased risk of malignancy.33 Calcitonin testing for patients with thyroid nodules is controversial. An elevated calcitonin suggests medullary thyroid cancer but the yield is low. It is not recommended by most guidelines but there is a suggestion that calcitonin testing would be cost-effective in the United States.34 After history, physical examination, TSH, and cervical ultrasound, the next decision is whether or not a thyroid nodule needs
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to be biopsied. Typically, the decision depends upon the size of the nodule, ultrasound features of the nodule, and other clinical risk factors. Solid nodules greater than 1.0 cm in diameter should usually be biopsied; however, biopsy may be warranted in smaller nodules in patients with high-risk clinical features. Ultrasound features of nodules that increase the risk of malignancy include microcalcifications, hypoechogenicity, increased vascularity within the nodule, irregular nodule margins, and disruption of the thyroid capsule.35,36 Ultrasound findings that decrease the chance of malignancy include simple cysts (malignancy is rare and biopsy for diagnosis is not indicated) and spongiform appearance. Highrisk clinical features include history of radiation exposure, history of a syndrome with increased thyroid cancer risk, family history of thyroid cancer in a first-degree relative, or a thyroid abnormality discovered to be FDG avid on PET scanning.17,37 Fine-needle aspiration (FNA) can usually be performed in cooperative patients with only local anesthesia; however, some children require sedation or even general anesthesia. The need for general anesthesia makes decision-making more complex. Performing FNA under ultrasound guidance is recommended to increase the yield of adequate biopsies and is especially useful when the nodules are small or when previous biopsies have been nondiagnostic.17 FNA results may be classified as nondiagnostic, benign, follicular or Hürthle cell neoplasm, follicular lesion of undetermined significance, or definite or suspicious for malignancy.17,38 If the FNA is nondiagnostic because of insufficient biopsy material then the patient may be followed and the FNA repeated under ultrasound guidance. When FNA is repeatedly nondiagnostic, patients require close follow-up with ultrasound and thyroid lobectomy and isthmusectomy are considered for definitive diagnosis. If the biopsy is benign then the patient can be followed up by physical examination and ultrasound. There is a small risk of false-negative FNA, so if the lesion enlarges, then the FNA may be repeated or surgical resection considered. FNA showing an indeterminate cytology of either follicular neoplasm or Hürthle cell neoplasm and FNA showing atypia or a follicular lesion of undetermined significance are traditional reasons for lobectomy and isthmusectomy because of a 5–10% risk of malignancy for a follicular lesion of undetermined significance and 20–30% risk of malignancy for follicular or Hürthle cell neoplasms. Surgical resection was necessary because the histologic determination of follicular or Hürthle cell malignancy depends upon finding vascular or capsular invasion, which requires examination of the entire lesion. There is some suggestion that Hürthle cell changes alone may not require surgical resection,39 and there is hope that molecular diagnostic markers may define the patients in these indeterminate groups who are at higher risk of malignancy and allow low-risk patients to avoid surgery.17 When the FNA shows thyroid cancer or is suspicious for cancer, then the patient should undergo primary surgical treatment as discussed below.
Thyroid cancer The incidence of thyroid cancer is increasing in adults and children, and there were an estimated 60,000 new cases in the United States in 2013.40 The overwhelming majority of cases are adults but incidence rate begins to rise in adolescence and it is one of the most frequent solid tumors of adolescents and young adults.41 When only children and adolescents are considered, there are an estimated 300–400 cases per year making thyroid cancer one of the more common solid tumors of childhood. The pathology of thyroid cancer is similar in adults and children. Of 1753 thyroid cancers in children reported to the SEER database,
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83% were papillary thyroid cancer, 10% were follicular thyroid cancer, 5% medullary thyroid cancer (MTC), and 2% were “other” types of thyroid cancer.42 As in adults, the primary treatment of thyroid cancer in children is surgery. The major questions of surgical treatment are the following: (1) How much thyroid needs to be removed? (2) Is regional lymph node resection required, and if so, how extensive does this need to be?43 As for adults, it is useful to consider papillary and follicular thyroid cancers together as “differentiated” thyroid cancers since their evaluation and management are very similar. MTC is very different and will be considered separately. When MTC is discovered on biopsy, then preoperative evaluation is done to stage the disease and assess for associated abnormalities. The extent of the disease is evaluated with ultrasound of the central and lateral neck to assess for lymphadenopathy. Calcitonin and carcinoembryonic antigen (CEA) serve as valuable tumor markers so their levels are checked. An in-depth family history, RET mutation evaluation, screening for pheochromocytoma, and serum calcium determination are done to assess for familial MTC and MEN2. The primary surgical treatment of MTC is a total thyroidectomy with bilateral central (level VI) lymph node resection.28 More extended lymph node dissection is done if there is evidence of further lymph node involvement. The other common clinical scenario involving MTC in children is the asymptomatic patient who presents after screening evaluation shows a RET mutation that places them at risk for MTC. These patients require total thyroidectomy. The timing of their operation is guided by the specific mutation28 and how the family judges the risks of developing MTC versus the risks of the operation. The need for central node dissection is more debatable in the setting of prophylactic thyroidectomy in patients with RET mutations but no evidence of MTC. When differentiated thyroid cancer is found on FNA, then ultrasound evaluation of lymph nodes of the central and lateral neck is done. This evaluation is important since spread to lymph nodes is common and clinical evidence of gross disease in regional lymph nodes will drive the decision for lymph node dissection. Ultrasound detection of lymph node abnormalities in the central neck is more difficult because of the adjacent thyroid, spine, and trachea. The accuracy of ultrasound is dependent upon the skill and experience of the sonographer. FNA of suspicious lymph nodes may be performed to define metastatic disease and determine the need for lymph node resection. For adults and children with differentiated thyroid cancer, guidelines generally recommend total thyroidectomy for tumors larger than 1 cm or more in diameter, if the tumor extends beyond the capsule of the thyroid, if metastases are present, if multifocal disease suspected, or if the patient is at high risk for recurrence.17 This recommendation is supported by an analysis of 50,000 patients that showed that total thyroidectomy for tumors 4 1 cm resulted in fewer recurrences and improved survival.44 Total thyroidectomy is also the recommended operation for thyroid cancer in children and it is being increasingly utilized.45 Central and lateral neck dissection is recommended for patients with any involved lymph nodes to improve local and regional control. Prophylactic lymph node dissection is debatable46 and is not generally recommended for children at this time. When differentiated thyroid cancer is discovered on the pathological examination of partial thyroid resections, then completion thyroidectomy is recommended.17 However, some argue that lobectomy and isthmusectomy followed by radioiodine ablation of remaining thyroid tissue and suppression of TSH with thyroid hormone replacement leads to excellent long-term survival.47 The ideal adjuvant treatment for children with thyroid cancer following primary surgery is unclear. Postoperative treatment with radioactive iodine is based on upon the size of the original tumor,
the completeness of surgical excision, and presence of metastases.48 Radioactive iodine is used after surgery to image for metastatic disease, to treat residual tumor and metastases, and to ablate any remaining normal thyroid tissue to allow more accurate monitoring for recurrent disease.17 Radioactive iodine used for therapy (131-Iodine) kills cells by emitting beta radiation. The penetration of the radiation is only 1–2 mm, so the effectiveness of 131-Iodine depends upon its uptake and concentration by the target cells. This is why 131-Iodine is effective against differentiated thyroid cancers but not against the malignant neuroendocrine cells of MTC. The uptake of iodine and radioactive iodine depends upon TSH stimulation and relative iodine insufficiency. This is the reason that patients require special preparation with limited dietary intake of iodine and sometimes stimulation with TSH before studies and treatment with radioactive iodine. The need for a target cell to actively concentrate iodine is the reason why it is important to avoid large doses of iodinated contrast agents that are typically given with CT scans with intravenous contrast. The excess iodine saturates thyroid tissue and complicates postoperative radioiodine diagnostic scanning and may delay treatment with therapeutic radioiodine for weeks to months.48 The outlook for children with thyroid cancer is remarkably favorable, even more favorable than adults with the disease. Even though children tend to present with more advanced disease, they typically respond well to treatment. In a review of 540 children from nine centers, the recurrence rate was 10–35% but only 13 of the 540 patients died of their disease 12–33 years after their operation.49 The largest group of patients analyzed were 1753 children in the SEER database report mentioned previously; 93% of the group had differentiated thyroid cancers and their postoperative survivals at 5, 15, and 30 years were all greater than 90%.42
Conclusions Although, in general, thyroid problems needing operative intervention are much more frequent in adults, thyroid surgery is an important part of the comprehensive care of children and adolescents. For thyroid nodules and thyroid cancers, the low numbers of pediatric cases, high cure rates, prolonged survival of patients with persistent or recurrent disease, changing patterns of staging, and lack of randomized, controlled trials make definitive recommendations for individual children difficult. However, despite these challenges it seems that, for the most part, the guidelines for care of adults can be extrapolated to children and their thyroid nodules can be effectively evaluated with ultrasound and FNA. In addition, treatment of children with thyroid cancer by total thyroidectomy, central and lateral lymph node dissection for those with clinical or imaging evidence of node involvement, and postoperative radioiodine is extremely successful. The ideal process to provide the best possible outcomes for children with surgical thyroid diseases requires a team of physicians and surgeons who have expertise and experience in the care of children and who can successfully collaborate with adult specialists to provide high-quality, cutting-edge care in a setting that has the optimal resources to care for children and adolescents. References 1. Fancy T, Gallagher D 3rd, Hornig JD. Surgical anatomy of the thyroid and parathyroid glands. Otolaryngol Clin North Am. 2010;43(2):221–227. 2. Miller BS, Gauger PG. Thyroid gland. In: Mulholland M, Lillemoe K, Doherty G, Maier R, Simeone D, Upchurch G, editors. Greenfield's Surgery. 5th ed, Philadelphia: Lippincott Williams & Wilkins; 2011. p. 1282–1302. 3. Organ GM, Organ CH Jr. Thyroid gland and surgery of the thyroglossal duct: exercise in applied embryology. World J Surg. 2000;24(8):886–890. 4. Ellis PD, van Nostrand AW. The applied anatomy of thyroglossal tract remnants. Laryngoscope. 1977;87(5 Pt 1):765–770.
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