• Thyroid nodules are typically recognized when a physician or patient palpates a central neck mass, or they are discovered incidentally on imaging studies performed for other reasons.
• Ninety-five percent of thyroid nodules are benign, and thyroid ultrasound is the best overall imaging study to evaluate characteristics of thyroid nodules and to determine which nodules may require fine-needle aspiration biopsy.
• Ultrasound-guided fine-needle aspiration biopsy is often performed at the time of thyroid ultrasound for thyroid nodules that have suspicious sonographic features.
• Fine-needle aspiration histopathology can aid in diagnosis of thyroid cancer, but fine-needle aspiration cytology reports often fall into an indeterminate thyroid lesion/neoplasm category.
• Thyroid cancer does not typically affect thyroid hormone levels, but thyroid-stimulating hormone (TSH) should be measured in the workup of a thyroid nodule and to assess thyroid function prior to consideration of thyroid surgery.
• Medullary thyroid carcinoma is a rare type of thyroid cancer that can be diagnosed by fine-needle aspiration biopsy and/or elevated serum calcitonin and carcinoembryonic antigen (CEA) levels in the presence of a thyroid mass.
• Twenty percent of medullary thyroid carcinoma is hereditary and associated with autosomal dominant mutations in the RET proto- oncogene (MEN syndrome); therefore all patients with medullary thyroid carcinoma should undergo RET genetic testing and evaluation for pheochromocytoma prior to surgery.
• Anaplastic thyroid carcinoma is a rare and extremely aggressive form of thyroid cancer that presents as a very rapidly growing thyroid mass.
• Observation with follow-up ultrasound is the most appropriate treatment recommendation for thyroid nodules that are suspected to be benign unless the patient is having compressive symptoms related to a large benign thyroid tumor or goiter.
• Thyroid nodules that are indeterminate for malignancy on fine- needle aspiration biopsy may be treated with short-term observation, thyroid lobectomy, or total thyroidectomy.
• Micropapillary thyroid carcinomas (tumors < 1 cm) can be treated with short-term observation, thyroid lobectomy, or total thyroidectomy, depending on patient age and preference.
• Well-differentiated thyroid cancers (papillary and follicular thyroid cancers) may be treated with thyroid lobectomy or total thyroidectomy, with or without central compartment lymph node dissection.
• For patients with intermediate or high risk well-differentiated thyroid cancers who undergo total thyroidectomy, radioactive iodine and thyroid hormone suppression may be considered following surgery.
• Total thyroidectomy with central compartment dissection is the recommended treatment for patients with medullary thyroid cancer.
• Postoperative external beam radiation therapy is rarely indicated for patients with well-differentiated thyroid cancer or medullary thyroid cancer unless disease is significantly invasive.
• Cytotoxic chemotherapy is not effective for well-differentiated thyroid cancer, but select molecular targeted therapies have been- approved by the Food and Drug Administration (FDA) for patients with progressive systemic disease.
Thyroid nodules are very common, affecting approximately 20% of the population. The vast majority (approximately 95%) of thyroid nodules are benign. The incidence of thyroid nodules increases with age, and thyroid nodules are more common in females. The clinical importance of thyroid nodules lies in the need to exclude thyroid cancer, present in approximately 5% to 10% of thyroid nodules.
Thyroid cancer represents the most rapidly increasing cancer (> 5% increase per year in both men and women) in the United States and the most common endocrine malignancy. Thyroid cancer is more common in females, representing the fifth most common malignancy in women in the United States (6% of estimated cancer diagnoses in females in 2016); and is also relatively more common in young adults, representing 15% of overall U.S. cancer diagnoses among persons aged 20 to 34. However, the increasing incidence of thyroid cancer in the United States is largely attributed to higher rates of detection with increasing use of imaging such as neck ultrasonography. A recent study estimated that almost one-half of papillary thyroid cancers diagnosed in women and men less than 50 years old in the United States may be clinically irrelevant. Fortunately, thyroid cancer is most often an indolent malignancy, and many patients with thyroid cancer can live unknowingly with disease for years or even decades. Despite increased incidence, mortality from thyroid cancer remains very low (approximately 5%). Patients who die of thyroid cancer most often present with aggressive histopathology, high tumor burden, and distant metastases.
Ninety-five percent of thyroid cancers are not associated with any known risk factor. History of ionizing radiation to the thyroid is the only known environmental factor associated with increased risk of thyroid cancer, but this risk factor accounts for less than 1% of thyroid malignancies. Only 5% to 10% of patients with nonmedullary differentiated thyroid cancer have a familial occurrence, and well- differentiated thyroid cancer is generally not considered familial (familial follicular cell–derived differentiated thyroid cancer) unless three or more first-degree relatives are affected. Therefore routine screening for thyroid cancer with thyroid ultrasound is not recommended unless the patient has a specific genetic syndrome that may be associated with differentiated thyroid cancer, such as phosphate and tensin homolog hamartoma tumor syndrome (PTEN), Cowden disease, familial adenomatous polyposis (FAP), or Carney complex. On the other hand, approximately 20% of patients with medullary thyroid carcinoma (MTC) have multiple endocrine neoplasia (MEN) types 2A and 2B hereditary syndromes, and therefore patients with MTC should routinely undergo genetic testing.
The thyroid gland has two distinct hormone-producing cell types from which tumors arise: follicular cells and neuroendocrine parafollicular C cells. The follicular cells secrete thyroid hormone and are the origin of five types of thyroid cancer: papillary thyroid cancer, follicular thyroid cancer, Hurthle cell thyroid cancer, poorly differentiated thyroid cancer, and anaplastic thyroid cancer.
Medullary thyroid carcinoma, on the other hand, arises from the calcitonin-secreting parafollicular C cells (Table 1).
Classification, Genetics, and Incidence of Thyroid Cancers
Abbreviation: TKR = tyrosine kinase receptor.
Included among follicular thyroid cancers
Differentiated Thyroid Cancers
Papillary and follicular cancers are collectively referred to as differentiated thyroid cancers, indicating cells that maintain a microscopic appearance more similar to normal thyroid tissue. Differentiated thyroid cancer collectively makes up 95% of thyroid cancer. Papillary thyroid cancer is the most prevalent thyroid cancer subtype, and 70% have genetic alterations causing activation of the mitogen-activated protein kinase (MAPK) pathway. The MAPK pathway is most typically initiated by activation of the tyrosine kinase receptor. Activation of the MAPK pathway often leads to oncogenic conversion of BRAF, which is the most common genetic event in papillary thyroid cancer. Therefore tyrosine kinase and BRAF inhibition represent two foci of targeted drug therapy for rare cases of advanced and/or metastatic differentiated thyroid cancer. The two most common genetic mutations associated with follicular thyroid cancer are renin-angiotensin system (RAS) and paired box 8/peroxisome proliferator-activated receptor gamma (PAX8-PPARG) mutations.
Hurthle cell carcinomas are considered variants of differentiated follicular thyroid cancer that are distinguished by an accumulation of Hurthle cells. Thyroid Hurthle cells (also called oncocytic cells) are characterized by abundant eosinophilic granular cytoplasm as a result of accumulation of altered mitochondria. This phenomena of Hurthle cell change in the thyroid occurs in inflammatory disorders such as thyroiditis and Graves disease, and the notation of Hurthle cells is therefore common with fine-needle aspiration biopsies in which there is associated thyroiditis. The proliferation of oncocytes also may give rise to hyperplastic and neoplastic nodules termed Hurthle cell neoplasms.
Dedifferentiated thyroid cancers
Dedifferentiated thyroid cancers are very rare and include poorly differentiated and anaplastic thyroid cancers. Many tumors with poorly differentiated and anaplastic thyroid carcinoma exhibit areas or separate foci of papillary or follicular carcinoma, suggesting that these tumors may arise from preexisting well-differentiated tumors. Poorly differentiated thyroid cancers include tumors with solid/trabecular/insular growth patterns, absence of typical nuclear features of papillary thyroid carcinoma, high mitotic figures, and extensive tumor necrosis. Anaplastic thyroid cancers are similarly thought to derive from a terminal dedifferentiation of carcinoma of the thyroid follicular cell, often with loss of p53 and other genetic mutations. Histopathologically, anaplastic thyroid cancers appear as necrotic and hemorrhagic tumors with cytologic anaplasia showing bizarre tumor cells, high mitotic rate, and significant angioinvasion.
Dedifferentiated thyroid cancers exhibit rapid growth, high rates of distant metastases, and overall poor prognosis; anaplastic thyroid carcinomas are almost uniformly fatal.
Medullary thyroid cancers
MTCs originate from the neuroendocrine parafollicular C cells of the thyroid gland. Approximately 20% of MTC is hereditary, associated with germline mutations in the RET proto-oncogene, leading to MEN. Ninety-five percent of hereditary MTC is related to MEN2a (50% incidence parathyroid hyperplasia, 100% incidence MTC, and 33% incidence pheochromocytoma), whereas approximately 5% results from MEN2b (85% incidence MTC, 50% incidence pheochromocytoma, 80% incidence marfanoid body habitus, 100% incidence mucosal neuromas). Approximately 50% of patients with sporadic MTC have somatic RET mutations. The M918T mutation portends the worst prognosis in both hereditary and sporadic MTC.
The diagnosis of thyroid cancer is often made after incidental discovery of a nonpalpable thyroid nodule on radiology scans performed for unrelated reasons (eg, CT of the neck in the emergency room for a young woman in an automobile accident, or screening carotid ultrasound for an elderly woman with atherosclerosis). Some patients may undergo thyroid ultrasound after self-palpating a thyroid nodule or neck mass, or after their primary care physician palpates a thyroid nodule on routine physical examination. Patients with larger thyroid cancers may have presenting symptoms of hoarseness (caused by recurrent laryngeal nerve paralysis), dysphagia (caused by esophageal compression or invasion), difficulty breathing, or pain. Patients with advanced medullary thyroid cancer can have diarrhea, Cushing syndrome, or facial flushing because of high serum levels of calcitonin and other hormonally active peptides. However, the vast majority of small thyroid cancers are asymptomatic.
Serum TSH should be measured in the evaluation of a thyroid nodule, as rarely thyroid nodules can be hyperfunctioning. If serum TSH is subnormal in the presence of a thyroid nodule a radionuclide thyroid scan may be considered; “hot” nodules, that is those with uptake greater than the surrounding thyroid tissue, very rarely represent malignancy and do not require cytologic evaluation.
All patients with thyroid nodules should be evaluated with thyroid ultrasound. Ultrasound-guided fine-needle aspiration biopsy is the gold standard in diagnosis of thyroid neoplasia. However, not all thyroid nodules require biopsy. The vast majority of thyroid cancers are solid, and purely cystic nodules are very rarely malignant.
Nodules greater than 1 cm with suspicious sonographic features (e.g., solid nodules with irregular margins, microcalcifications, and/or increased central internal vascularity) are recommended for biopsy, but nodules less than 1 cm are rarely recommended for biopsy.
Incidental thyroid nodules that are discovered as fluorodeoxyglucose- avid on positron emission tomography (PET) imaging (“PET incidentalomas”) are recommended to undergo fine-needle aspiration biopsy, as PET-avid nodules have approximately 40% malignancy risk.
Thyroid cytologic classification is according to the criteria and terminology of the Bethesda system and includes the following general diagnostic categories (with associated malignancy risk): nondiagnostic (20% risk), benign (2% risk), follicular lesion (5–10% risk), follicular neoplasm (15–20% risk), atypical cells of undetermined significance (25% risk), suspicious for malignancy (90% risk), and malignant (99% risk). Papillary thyroid carcinoma can be diagnosed cytologically based on atypical nuclear features such as nuclear grooves and nuclear inclusions. In contrast to papillary thyroid carcinomas, follicular and Hurthle cell carcinomas can rarely be diagnosed on fine-needle aspiration biopsy, because the diagnostic criterion for diagnosis of malignancy requires demonstration of capsular or vascular invasion. Nondiagnostic fine-needle aspiration biopsies fail to meet criteria for cytologic analysis, and repeat biopsy is recommended. Thyroid fine-needle aspirations (FNAs), which fall into the indeterminate category (follicular lesion, follicular neoplasm, atypical cells of undetermined significance) may be further evaluated with molecular testing by one of several commercially available gene expression classifier tests (eg, Afirma) or individual mutational analysis (e.g., BRAF).
If thyroid cytology is suspicious for medullary thyroid carcinoma, serum calcitonin and CEA should be measured. Although CEA may be elevated with a number of malignancies, calcitonin is more specific to medullary thyroid carcinoma, and calcitonin can rarely be elevated in association with other conditions. Patients with MTC should undergo genetic testing prior to surgery to rule out hereditary MTC since a coexisting pheochromocytoma has the potential to cause hypertensive crisis during thyroid surgery. Often patients with hereditary MTC with associated pheochromocytoma will undergo resection of the pheochromocytoma before their thyroid surgery.
Differentiated Thyroid Cancer
Treatment algorithms for nondiagnostic, benign, indeterminate, and differentiated malignant thyroid nodules are illustrated in Box 1. For patients with indeterminate thyroid nodules a molecular gene expression classifier test or individual mutational analysis may be considered to further characterize preoperative risk of malignancy.
Determination of observation versus thyroid lobectomy must primarily take into account patient preference after discussion of risks, implications, and benefits of both approaches.
|Management of Thyroid Neoplasms and Cancers Based on Fine-Needle Aspiration Cytology|
Repeat ultrasound-guided fine-needle aspiration biopsy in 3 months If repeat biopsy nondiagnostic: Observation (with initial follow-up ultrasound 3–6 months) or thyroid lobectomy
Observation, may repeat ultrasound in 12 months
Indeterminate (Follicular lesion or follicular neoplasm or atypical cells of undetermined significance)
Observation (with initial follow-up ultrasound 3–6 months) or thyroid lobectomy
• May consider gene expression classifier test
Suspicious or Malignant Differentiated Thyroid Cancer
Thyroid lobectomy or total thyroidectomy with possible central compartment lymph node dissection
• Observation may be considered for older patients with intrathyroidal micropapillary (< 1 cm) carcinomas
• Thyroid hormone suppression and radioactive iodine may be considered postoperatively if total thyroidectomy performed
Medullary Thyroid Cancer
Total thyroidectomy with central compartment dissection
• Measure serum calcitonin/CEA and perform genetic testing (rule out MEN2 with associated pheochromocytoma) preoperatively
Differentiated thyroid cancer is generally treated with surgery, with the exception of intrathyroidal micropapillary carcinomas (tumors < 1 cm), which may be observed with follow-up ultrasound, especially in older patients. With micropapillary thyroid carcinoma, risk of rapid growth is low, and many of these lesions demonstrate relatively little growth over the course of 5- or 10-year follow-up.
For tumors between 1 and 4 cm, thyroid lobectomy may be considered in the absence of central compartment lymphadenopathy; total thyroidectomy is recommended for tumors greater than 4 cm.
Central compartment (i.e., level VI paratracheal) lymph node dissection should be performed for patients with lymph node metastases, and may be performed electively for patients with larger tumors because of the risk of occult lymph node metastases.
Intraoperative frozen section evaluation of central compartment lymph nodes may also be useful to guide the decision regarding central compartment lymph node dissection. Patients with lateral neck (most commonly levels II, III, IV, and VB) lymph node metastases should undergo selective comprehensive lateral neck dissection of aforementioned compartments. Single node plucking or “berry- picking” is not recommended, as this increases potential morbidity with any subsequent surgery to remove remaining lymph nodes.
Following total thyroidectomy patients with well-differentiated thyroid cancer are recommended for thyroid hormone suppression (suppression of TSH), since TSH is a trophic hormone that stimulates growth of thyroid follicular cells. Additionally, patients with distant metastases and/or higher risk tumors may be considered for postoperative radioactive iodine therapy. Postoperative external beam radiation therapy is very rarely indicated for well-differentiated thyroid cancer, but is only indicated with particularly aggressive and invasive disease in patients who would not be candidates for future revision surgery (e.g., laryngotracheal invasion, or esophageal invasion). Traditional cytotoxic chemotherapeutic agents are ineffective for well-differentiated thyroid cancer, but select targeted molecular therapies may be considered for patients with progressive and/or symptomatic disease. Sorafenib and lenvatinib are two small molecule kinase inhibitors that have been approved by the U.S. Food and Drug Administration for advanced and/or metastatic thyroid cancer refractory to radioactive iodine.
Approximately 25% of patients undergoing thyroid lobectomy will require thyroid hormone replacement, in addition to all patients undergoing total thyroidectomy. These patients require follow-up to check thyroid function tests, and also surveillance testing to detect potential recurrent differentiated thyroid cancer. Depending on prognostic variables, up to 30% of patients with well-differentiated thyroid cancer may develop recurrence over the course of several decades following initial therapy. Thyroid/cervical ultrasound and serum thyroglobulin measurement (for patients who have had total thyroidectomy) are the two primary methods of long-term follow-up for patients with history of well-differentiated thyroid cancer. Whole body diagnostic radioactive iodine scans are less sensitive for detecting recurrent disease, but can be useful for localizing disease in the presence of detectable/rising thyroglobulin in the absence of thyroid bed/neck disease (as assessed by ultrasound or computed tomography [CT] imaging), or in select high risk patients whose serum thyroglobulin is unreliable for detection of thyroid disease because of the presence of thyroglobulin antibodies. Serum thyroglobulin can be measured while the patient is on thyroid hormone, or under conditions of stimulation, either by thyroid hormone withdrawal, or administration of recombinant TSH. Stimulated thyroglobulin is more sensitive for detecting residual thyroid tissue and/or recurrent disease.
Ultrasound-guided fine-needle aspiration biopsy can be performed for recurrent thyroid bed or lateral neck nodules/lymph nodes. Small burden recurrent locoregional or distant disease may be monitored for a period of time, because the majority of well-differentiated thyroid cancer is slow growing and asymptomatic in the absence of large tumor burden. Alternatively, surgery may be performed for larger recurrent nodules/lymph nodes, and radioactive iodine and/or targeted molecular therapy may be considered for progressive distant disease.
Medullary Thyroid Cancer
As with differentiated thyroid cancer, surgery is the mainstay of treatment for medullary thyroid cancer. Infants and children with hereditary MTC diagnosed on genetic testing require special consideration; patients with intermediate risk mutations may be recommended for prophylactic thyroidectomy by 5 years of age, whereas patients with MEN2b and high risk mutations may be recommended for prophylactic thyroidectomy in the first year of life.
Occult cervical lymph node metastases with MTC are common, and therefore total thyroidectomy and bilateral central compartment paratracheal lymph node dissection is the generally recommended surgery. For patients with evidence of lateral neck disease on preoperative imaging, a systematic unilateral or bilateral selective or modified radical neck dissection should be performed, preserving important neurovascular structures unless they are invaded with disease. Most commonly cervical levels II, III, IV, and VB are dissected, although patients may rarely have metastases to other levels of the lateral neck. For patients without preoperative lateral neck disease, observation of the lateral neck is appropriate, as these patients can undergo subsequent lateral neck surgery if they were to later develop lateral neck metastases. Some surgeons, however, recommend elective unilateral or bilateral lateral neck dissection at the time of the thyroid surgery for patients with serum calcitonin greater than 20 (elective unilateral dissection) or 200 (elective bilateral dissection).
External beam radiation therapy is only indicated postoperatively for patients with particularly aggressive and invasive disease who would not be candidates for future revision surgery (e.g., laryngotracheal invasion or esophageal invasion). Since medullary thyroid cancer is not a follicular neoplasm there is no indication for thyroid hormone suppression postoperatively. Patients should be managed with appropriate thyroid hormone supplementation so that their TSH is maintained in the euthyroid range. Radioactive iodine is not indicated in the postoperative treatment of medullary thyroid cancer because parafollicular C cells (and thereby medullary thyroid cancer cells) do not take up radioactive iodine.
Measurement of serum calcitonin and CEA is the primary method of surveillance for recurrence and/or distant metastases, and should be measured approximately 3 months postoperatively and at regular intervals thereafter. Rising tumor markers should prompt further evaluation with cross-sectional imaging of the neck, chest, and abdomen, in addition to consideration of bone scan. Higher levels of calcitonin (> 1000) are associated with distant metastases, and shorter calcitonin doubling time has been associated with overall poorer prognosis.
Medullary thyroid cancers have variable growth rates, and locoregionally recurrent and distant disease may be monitored in the absence of significant progression or symptoms. Patients with progressive or symptomatic recurrent and/or distant disease may be treated surgically (for patients with operable locoregional recurrence) or with systemic targeted molecular therapy. Vandetanib and cabozantinib are tyrosine kinase inhibitors with activity against RET and vascular endothelial growth factor receptor (VEGFR) with U.S. FDA approval for use in advanced medullary thyroid cancer. Patients with symptomatic diarrhea resulting from markedly elevated serum calcitonin should be treated with antimotility agents such as loperamide, diphenoxylate/atropine, or codeine.
Anaplastic Thyroid Cancer
Because of rapid growth (doubling time often measured in weeks) and frequent distant metastases, anaplastic thyroid cancer is almost always uniformly fatal. Patients with anaplastic thyroid cancer often have rapid onset of speech, swallowing, and breathing difficulties, and the decision for a tracheotomy in these patients is based on discussion of risks and implications with the patient. Anaplastic cancers confined to the thyroid gland are rare, but surgery and postoperative chemoradiation therapy can be effective to control disease in this very select group of anaplastic thyroid cancer patients. Unfortunately, the vast majority of patients with anaplastic thyroid cancer present with massive tumor burden beyond the thyroid gland and/or distant metastases, and surgery is generally not effective to control disease in these situations. These patients may be treated palliatively with radiation, chemotherapy, or both; or they may elect for supportive/hospice care.
Since thyroid cancer is generally treated surgically, operative treatment complications are most common. Significant care must be taken to identify and preserve the bilateral recurrent laryngeal nerves during thyroid surgery; injury to unilateral or bilateral recurrent laryngeal nerves may result in temporary or permanent postoperative hoarseness (unilateral paralysis), or breathing difficulty (bilateral paralysis). Patients with a bilateral vocal cord paralysis may require a temporary or permanent tracheostomy tube. Permanent unilateral recurrent laryngeal nerve paralysis occurs following approximately 1% to 2% of thyroid surgeries.
A second postoperative complication associated with total thyroidectomy is hypocalcemia related to hypoparathyroidism. Care must be taken during thyroid surgery to preserve the bilateral superior and inferior parathyroid glands along with their respective vascular pedicle. Although one normal-functioning parathyroid gland is generally considered sufficient for long-term parathyroid function, many patients become temporarily hypoparathyroid, and hypocalcemic when multiple parathyroid glands are removed and/or devascularized during thyroid and central compartment surgery.
Since the inferior parathyroid gland is usually interspersed with central compartment lymph nodes, this gland is often devascularized with central compartment surgery. Any devascularized parathyroid gland should be reimplanted, generally in an adjacent muscle such as the sternothyroid or sternocleidomastoid muscle. Patients who undergo total thyroidectomy should have their calcium and/or parathyroid hormone level checked in the immediate postoperative period prior to discharge. If calcium and/or parathyroid hormone level is low, an appropriate calcium replacement protocol should be initiated. Most postoperative hypocalcemia and hypoparathyroidism is temporary, with permanent hypoparathyroidism occurring in approximately 3% of thyroid surgery.
Patients who undergo lateral neck surgery in association with thyroid surgery have additional risks of neurovascular injury, which includes shoulder weakness (cranial nerve 11 injury), tongue weakness (cranial nerve 12 injury), lower lip weakness (marginal mandibular nerve injury), and chyle leak.
Risks of radioactive iodine include sialadenitis, dry mouth, and altered taste. There are also rare reports of second cancers that may be associated with cumulative high doses of radioactive iodine. Women who are nursing or pregnant should not receive radioactive iodine, and patients are recommended that close contact with others, especially children, should be avoided for several days following administration of radioactive iodine.
Thyroid nodules are very common and 95% are benign. The gold standard for evaluation of a thyroid nodule is ultrasound-guided fine- needle aspiration biopsy. Benign and many indeterminate nodules may be observed, although thyroid cancer is generally treated with surgery. Most well-differentiated thyroid cancers (papillary and follicular) have good prognosis with surgery (either thyroid lobectomy or total thyroidectomy), and some patients are recommended for postoperative radioactive iodine and thyroid hormone suppression. Medullary thyroid cancer is typically treated with total thyroidectomy and central compartment lymph node dissection. Approximately 20% of medullary thyroid carcinomas are hereditary, associated with MEN2, and mutation in the RET proto- oncogene; patients with medullary thyroid cancer should therefore undergo genetic testing prior to surgery. Postoperative radiation therapy is rarely indicated for well-differentiated or medullary thyroid cancers unless the disease is particularly aggressive and invasive. Anaplastic thyroid cancer is a very aggressive and almost uniformly fatal rare type of thyroid cancer that is commonly treated with palliative radiation therapy, and/or chemotherapy.
1. Francis G.L., Waguespack S.G., Bauer A.J., et al. Management guidelines for children with thyroid nodules and differentiated thyroid cancer: the American Thyroid Association Guidelines Task Force on Pediatric Thyroid Cancer. Thyroid. 2015;25:716–759.
2. Haughen B.R., Alexander E.K., Bible K.C., et al. 2015 American Thyroid Association management guidelines for adult patients with thyroid nodules and differentiated thyroid cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer. Thyroid. 2016;26:1–133.
3. NCCN Clinical Practice Guidelines in Oncology: Thyroid Carcinoma. Version 2.2015. Available at: NCCN.org. [accessed 16.05.16].
4. O’Grady T.J., Gates M.A., Boscoe F.P. Thyroid cancer incidence attributable to overdiagnosis in the United States 1981–2011. Int J Cancer. 2015;137:2664–2673.
5. Randolph G.W. Surgery of the thyroid and parathyroid glands. In: Randolph G.W., ed. 2nd ed. Philadelphia: Saunders; 2013.
6. Siegel R.L., Miller K.D., Jemal A. Cancer statistics, 2016. CA Cancer J Clin. 2016;66:7–30.
7. Wells Jr. S.A., Asa S.L., Dralle H., et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma: The American Thyroid Association Guidelines Task Force on Medullary Thyroid Carcinoma. Thyroid. 2015;25:567–610.