Management of Thyroid Neoplasms

Surgical Anatomy and Embryology

The thyroid medial anlage derives from the ventral diverticulum of the endoderm from the first and second pharyngeal pouches at the foramen cecum. The diverticulum descends from the base of the tongue to its adult pretracheal position through a midline anterior path with the primitive heart and great vessels during weeks 4 to 7 of gestation. The proximal portion of this structure retracts and degenerates into a solid, fibrous stalk; persistence of this tract can lead to the development of a thyroglossal duct cyst with variable amounts of associated thyroid tissue. The lateral thyroid primordia arise from the fourth and fifth pharyngeal pouches and descend to join the central component. Parafollicular C cells arise from the neural crest of the fourth pharyngeal pouch as ultimobranchial bodies and infiltrate the upper portion of the thyroid lobes. Because of the predictable fusion of the ultimobranchial bodies to the medial thyroid anlage, C cells are restricted to a zone deep within the middle to upper third of the lateral lobes.

The thyroid gland is composed of two lateral lobes connected by a central isthmus that weighs 15 to 25 g in adults. A thyroid lobe usually measures about 4 cm in height, 1.5 cm in width, and 2 cm in depth. The superior pole lies posterior to the sternothyroid muscle and lateral to the inferior constrictor muscle and the posterior thyroid lamina. The inferior pole can extend to the level of the sixth tracheal ring. Approximately 40% of patients have a pyramidal lobe that arises from either lobe or the midline isthmus and extends superiorly ( Fig. 122.2 ).

The thyroid is enclosed between layers of the deep cervical fascia in the anterior neck. The true thyroid capsule is tightly adherent to the thyroid gland and continues into the parenchyma to form fibrous septa that separate the parenchyma into lobules. The surgical capsule is a thin, filmlike layer of tissue that lies on the true thyroid capsule. Posteriorly, the middle layer of the deep cervical fascia condenses to form the posterior suspensory ligament, or Berry ligament, that connects the lobes of the thyroid to the cricoid cartilage and the first two tracheal rings.

Blood supply to and from the thyroid gland involves two pairs of arteries, three pairs of veins, and a dense system of connecting vessels within the thyroid capsule. The inferior thyroid artery arises as a branch of the thyrocervical trunk ( Fig. 122.3 ). This vessel extends along the anterior scalene muscle and crosses beneath the long axis of the common carotid artery to enter the inferior portion of the thyroid lobe. Although variable in its relationship, the inferior thyroid artery lies anterior to the recurrent laryngeal nerve (RLN) in approximately 70% of patients. The inferior thyroid artery is also the primary blood supply for the parathyroid glands.

The superior thyroid artery is a branch of the external carotid artery and courses along the inferior constrictor muscle with the superior thyroid vein to supply the superior pole of the thyroid. This vessel lies posterolateral to the external branch of the superior laryngeal nerve (SLN) as the nerve courses through the fascia that overlies the cricothyroid muscle. Care should be taken to ligate this vessel without damaging the SLN. Occasionally, the arteria thyroidea ima may arise from the innominate artery, carotid artery, or aortic arch and may supply the thyroid gland near the midline. Many veins within the thyroid capsule drain into the superior, middle, and inferior thyroid veins, which lead to the internal jugular or innominate veins. The middle thyroid vein travels without an arterial complement, and division of this vessel permits adequate rotation of the thyroid lobe to identify the RLN and parathyroid glands.

The RLN provides motor supply to the larynx and some sensory function to the upper trachea and subglottic area. Careful management of thyroid carcinomas requires a thorough knowledge of the course of the RLN (see Fig. 122.3 ). During development, the inferior laryngeal nerves derive from the sixth branchial arch and originate from the vagus nerves under the sixth aortic arch. The RLN is dragged caudally by the lowest persisting aortic arches. On the right side, the nerve recurs around the fourth arch (subclavian artery), and on the left side, the nerve recurs around the sixth arch (ligamentum arteriosum).

The right RLN leaves the vagus nerve at the base of the neck, loops around the right subclavian artery, and returns deep to the innominate artery back into the thyroid bed approximately 2 cm lateral to the trachea ( Fig. 122.4 ). The nerve enters the larynx between the arch of the cricoid cartilage and the inferior cornu of the thyroid cartilage. The left RLN leaves the vagus at the level of the aortic arch and loops around the arch lateral to the obliterated ductus arteriosus. The nerve returns to the neck posterior to the carotid sheath and travels near the tracheoesophageal groove along a more medial course than the right RLN. The nerve crosses deep to the inferior thyroid artery approximately 70% of the time and often branches above the level of the inferior thyroid artery before entry into the larynx. The RLN travels beneath the inferior fibers of the inferior constrictor and behind the cricothyroid articulation to enter the larynx. A “nonrecurrent” laryngeal nerve may rarely occur on the right side and enters from a more lateral course ( Fig. 122.5C ; see also Fig. 122.3 ). In almost all cases of a nonrecurrent laryngeal nerve, an aberrant retroesophageal subclavian artery (arteria lusoria) or other congenital malformation of the vascular rings is present ( Fig. 122.6 ).

The SLN arises beneath the nodose ganglion of the upper vagus and descends medial to the carotid sheath, dividing into an internal and external branch about 2 cm above the superior pole of the thyroid. The internal branch travels medially and enters through the posterior thyrohyoid membrane to supply sensation to the supraglottis. The external branch extends medially along the inferior constrictor muscle to enter the cricothyroid muscle. Along its course, the nerve travels with the superior thyroid artery and vein. The nerve typically diverges from the superior thyroid vascular pedicle about 1 cm from the thyroid superior pole ( Fig. 122.7 ).

Proper management of the parathyroid glands during thyroid surgery is crucial to avoid hypoparathyroidism. The superior parathyroid glands are derived from the fourth pharyngeal pouch, whereas the inferior counterparts originate from the third pharyngeal pouch. The parathyroid glands are caramel-colored glands that weigh 30 to 70 mg. The subtle distinction of tan and yellow coloration permits differentiation from adjacent fatty tissue, although with trauma, the glands can become mahogany in color. Four parathyroid glands exist in 80% of patients, and at least 10% of patients have more than four glands. The glands are situated on the undersurface of the thyroid gland in predictable locations. The superior glands are located at the level of the cricoid cartilage, usually medial to the intersection of the RLN and the inferior thyroid artery. The inferior glands are more variable in location than their superior counterparts. These glands may be on the lateral or posterior surface of the lower pole ( Fig. 122.8 ). In many patients, the position of the parathyroid glands on one side is similar to the other side and should be a useful guide.

Molecular Basis for Thyroid Neoplasms

Numerous genetic and molecular abnormalities have been described in thyroid neoplasms, and specific genetic alterations of thyroid carcinoma are summarized in Table 122.1 . Similar to other head and neck cancers, an accumulation of genetic alterations seems to be required for progression to thyroid carcinoma. The specific molecular events and their order continue to be defined, and the current genome sequencing effort by the Cancer Genome Atlas of PTC should be quite informative.

Alterations noted in the development of thyroid carcinomas include changes in total cellular DNA content. The loss of chromosomes, or aneuploidy, has been noted in 10% of all papillary carcinomas but is present in 25% to 50% of all patients who die as a result of these lesions. Similarly, the development of follicular adenomas is associated with a loss of the short arm of chromosome 11 (11p), and transition to a follicular carcinoma seems to involve deletions of 3p, 7q, and 22q. Loss of heterozygosity that involves multiple chromosomal regions is much more prevalent in follicular adenomas and carcinomas than in papillary carcinomas.

Several oncogenes, altered genes that contribute to tumor development, have been identified in early thyroid tumor progression. Mutations in the thyroid-stimulating hormone (TSH) receptor and G-protein mutations are found in hyperfunctioning thyroid adenomas. These changes can lead to the constitutive activation of cell-signaling pathways, such as the adenylate cyclase–protein kinase A system. Point mutations of the G-protein Ras found in thyroid adenomas and multinodular goiters are believed to be an early mutation in tumor progression. Somatic Ras mutations are associated with follicular adenomas and, to a lesser extent, with follicular carcinomas. The resultant activation of the phosphatidylinositol 3′-kinase (PI3K) signal transduction pathway and AKT, a PI3K-related serine/threonine kinase, also seems to be specific to follicular thyroid carcinoma (FTC).

Other genetic changes have also been associated with certain types of thyroid carcinoma. Mutations within the mitogen-activated protein kinase pathway are involved in malignant transformation to PTC. Additionally, rearrangements or activation of RET or BRAF protooncogenes, which can also activate mitogen-activated protein kinase, are often found in PTC. Gene rearrangements that involve tropomycin receptor kinase A (TRKA) and the gene known as neurotropic tyrosine receptor kinase type 1 (NTRK1) , a receptor for nerve growth factor, are associated with PTCs. These rearrangements with heterologous sequences generate NTRK1 oncogenes that constitutively activate the tyrosine kinase domain. Mutations in MET /hepatic growth factor have been linked to PTC and poorly differentiated thyroid carcinoma (PDTC). Other growth factors such as fibroblast growth factors, epidermal growth factor, and vascular endothelial growth factor and their cognate receptors may have increased expression in thyroid tumors and can contribute to tumor progression. The transversion point mutation T1799A results in the BRAF-V600E mutant protein, which is a constitutively active form of this serine/threonine kinase. BRAF-V600E is present in approximately 45% of PTCs and in some cases can be associated with poor clinicopathologic outcomes, including aggressive pathologic features, increased recurrence, loss of radioiodine avidity, and treatment failures. Furthermore, this mutation is also found in approximately 45% of ATCs.

Different types of galectin, a carbohydrate-binding protein, seem to be differentially expressed in papillary and anaplastic carcinomas and can be useful in distinguishing benign from malignant thyroid lesions. In Cowden disease (familial goiter and skin hamartomas), inactivating mutations of the phosphatase and tensin homologue (PTEN) gene have been identified. PTEN may inhibit phosphorylation and kinase activity of AKT1, which leads to the development of follicular adenomas and carcinomas. The PAX8/PPARγ γ1 (peroxisome proliferator-activated receptor) rearrangement seems to be unique to FTC. PAX8 is expressed at high levels during thyroid development, and the PAX/PPARγ γ 1 gene product seems to function as a dominant negative that blocks the activation of wild-type PPARγ γ 1. Mutations in the tumor-suppressor gene TP53, a transcriptional regulator, seem to be involved in insular thyroid carcinomas and in the progression from papillary to anaplastic thyroid carcinoma (ATC). PDTC has a worse prognosis than WDTC and possesses genetic features in between WDTC and ATC.

The role of mutations of the RET oncogene in the development of PTC and MTC has been extensively studied. Located on chromosome 10, RET codes for a transmembrane tyrosine kinase receptor (TRK) that binds glial cell line–derived neurotrophic factor. During embryogenesis, RET protein is normally expressed in the nervous and excretory systems. Abnormalities in RET expression result in developmental defects that include the disruption of the enteric nervous system (Hirschsprung disease). Presumably, RET gene mutations result in the activation of the Ras/JNK/ERK1/2 signaling pathways, which results in further genomic instability and prevention of entry into the apoptotic pathway.

MTC and pheochromocytoma arise from neural crest cells that contain RET point mutations. These point mutations have been well documented in patients with familial MTC and multiple endocrine neoplasia (MEN) types 2A and 2B. The aggressiveness of the MTC that develops is linked to the specific RET mutation identified. Somatic mutations of RET are also found in approximately 25% of sporadic MTCs. Many of these are identical to the codon 918 mutation found as a germline mutation in MEN-2B, although other codons are more infrequently involved.

Rearrangements of the RET gene by fusion with other genes also create transforming oncogenes. Although more than 10 rearrangements have been described, three oncogene proteins—RET/PTC1, RET/PTC2, and RET/PTC3—account for most of the rearrangements found in PTCs and are more frequently associated with childhood thyroid carcinomas. Not all patients with papillary carcinomas express an RET/PTC gene, however. Geographic differences are marked, and the gene rearrangement is strongly associated with radiation exposure. After the Chernobyl nuclear disaster, 66% of the PTCs removed from affected patients had RET/PTC1 or RET/PTC3 rearrangements. The RET/PTC3 rearrangement is most commonly associated with a “solid” follicular variant of PTC, whereas RET/PTC1 is associated more often with the classic or diffuse sclerosing variants.

Molecular Diagnostics and Targeted Therapies

The increased understanding of underlying genetic alterations related to various subtypes of thyroid carcinoma have led to the development of diagnostic and prognostic assays. Molecular markers that include galectin-3, cytokeratin, and BRAF have been evaluated and may improve the diagnostic accuracy for patients with indeterminate thyroid nodules. Combined use of genetic markers in a gene-expression classifier has been validated in a prospective multicenter study. Furthermore, the BRAF-V600E mutation may assist in risk stratification and may define treatment for patients with PTC and ATC. Although these tests are becoming commercially available, widespread clinical adoption depends upon further validation.

Targeted therapies have focused upon the known oncogenic signaling pathways, modulators of growth or apoptosis, and angiogenesis inhibitors. A number of phase II studies have demonstrated promising efficacy for novel small-molecule protein kinase inhibitors. Currently, cabozantinib and vandetanib (medullary thyroid cancer); lenvatinib and sorafenib (differentiated thyroid cancer); and combination dabrafenib/trametinib (anaplastic thyroid cancer) are the only Food and Drug Administration (FDA)–approved targeted agents for the treatment of advanced thyroid cancer. Continuing efforts are directed at genetic-based targeting of disease and restoration of radioiodine avidity.

Risk Factors and Etiology

Although the specific molecular events related to the development of thyroid carcinomas remain incompletely defined, several patient and environmental factors have been closely examined. Women are three times more likely than men to develop differentiated thyroid cancer and two times more likely to have ATC. The median age at diagnosis is 51 years, with a peak in women at 50 to 54 years and in men at 65 to 69 years. Epidemiologic studies have not shown a clear association between dietary iodine and thyroid carcinomas. Also, there does not seem to be a simple relationship between benign goiter and WDTC. Although PTC is not associated with goiter, follicular and ATCs occur more commonly in areas of endemic goiter. Additionally, two particularly important risk factors—exposure to radiation and a family history of thyroid cancer—have been studied extensively.

Exposure to ionizing radiation increases patient risk for the development of thyroid carcinoma. Ionizing radiation exposure is the only established environmental risk factor for thyroid cancer. Low-dose ionizing radiation treatments (<2000 cGy) were used in the treatment of enlarged thymus to prevent sudden crib death, enlarged tonsils and adenoids, acne vulgaris, hemangioma, ringworm, scrofula, and other conditions. The risk increases linearly from 6.5 to 2000 cGy and typically has a latency period that lasts 10 to 30 years. Although higher doses of ionizing radiation typically lead to the destruction of thyroid tissue, patients with Hodgkin disease who receive 4000 cGy also have a higher incidence of thyroid cancer. Palpable thyroid nodularity may be present in 17% to 30% of patients exposed to ionizing radiation. A patient with a history of radiation exposure who presents with a thyroid nodule has a 50% chance of having a malignancy. Of these patients with thyroid cancer, 60% have cancer within the nodule, and the remaining 40% have cancer in another area of the thyroid. Thyroid carcinoma tends to be papillary and is frequently multifocal, and the risk of cervical metastases is also higher.

Similarly, patients exposed to radiation from nuclear weapons and accidents have a higher incidence of thyroid cancer. Children near the Chernobyl nuclear power facility had a 60-fold increase in thyroid carcinoma after the nuclear accident in 1986. Most of these children were infants at the time of the accident, and many of these cases developed without the typical latency period. The thyroid gland seems to be particularly vulnerable to ionizing radiation in children and yet is relatively insensitive in adults. In the life-span study of atomic bomb survivors in Hiroshima and Nagasaki, the risk of thyroid cancer was associated with patient age at the time of the bombings. The risk was greatest for individuals younger than 10 years, and no increased incidence of thyroid cancer was seen in individuals older than 20 years at the time of exposure.

Finally, familial and genetic contributions need to be fully evaluated. A patient with a family history of thyroid carcinoma may require specific diagnostic testing. Approximately 6% of patients with PTC have familial disease. PTC occurs with increased frequency in certain families with breast, ovarian, renal, or central nervous system malignancies. Gardner syndrome (familial colonic polyposis) and Cowden disease are associated with WDTCs. Patients with a family history of MTC, MEN-2A, or MEN-2B warrant evaluation for the RET point mutation.

Tumor Staging and Classification

Numerous staging and classification systems have been devised to stratify patients with thyroid carcinomas. These classifications have identified key patient-specific and tumor-specific characteristics that predict patient outcome. Risk grouping has been used to focus aggressive treatment for high-risk patients and to avoid excessive treatment and its potential complications in patients with a lower risk for tumor recurrence or tumor-related death.

Evaluation of a Thyroid Nodule

The incidence of thyroid nodular disease is quite high, and it spontaneously occurs at a rate of 0.08% per year, starting in early life and extending into the eighth decade. Although thyroid nodules represent a wide spectrum of disease, most are colloid nodules, adenomas, cysts, and focal thyroiditis; only a few (5%) are carcinoma. With a lifetime incidence of 4% to 7%, the annual incidence of thyroid nodules in the United States is about 0.1%, which is approximately 300,000 new nodules each year. Most of these nodules are benign and do not require removal. With approximately 37,000 new thyroid cancers each year, about 1 in 20 new thyroid nodules contains carcinoma, however, and approximately 1 in 200 nodules is lethal. The challenge in treating patients with thyroid nodules is to identify patients with malignant lesions and to balance the potential morbidity of treatment with the aggressiveness of the disease.

Rational Approach to Management of a Thyroid Nodule

Numerous diagnostic algorithms have been proposed for the evaluation of a thyroid nodule ( Fig. 122.9 ). Evaluation generally begins with a thorough history and physical examination to identify significant risk factors. Surgery may be deemed appropriate based solely on high-risk factors such as age, sex, history of radiation exposure, rapid nodule growth, upper aerodigestive tract symptoms, and fixation.

Baseline TSH screening determines the diagnostic course. Patients with hyperthyroidism (suppressed serum TSH level) should receive radionuclide scanning to determine the presence of a toxic hot nodule, Marine-Lenhart syndrome, or Graves disease with a concomitant cold nodule. A patient with hypothyroidism (elevated serum TSH level) should be appropriately treated by an endocrinologist, and then FNAC should be performed. Most patients are euthyroid (normal serum TSH level), and FNAC should be performed. US examination can provide valuable diagnostic information, especially in the selection of a nodule for biopsy in a patient with multiple nodules, and it may facilitate FNAC. In a patient with a thyroid malignancy, evaluation of the nodal basins can detect early clinically occult disease and can alter surgical management. Patients with cytologic findings diagnostic or strongly suggestive of malignancy should be referred to a surgeon for removal of the lesion.

A diagnosis of follicular neoplasm by FNAC requires surgery to determine the presence of follicular adenoma, or papillary or follicular carcinoma. FNAC suspicious for medullary carcinoma may be subject to immunohistochemical (IHC) techniques to detect calcitonin. Before surgical intervention, a patient with FNAC suggestive of medullary carcinoma requires genetic studies and additional testing (discussed later in the section on MTC). Suspicious findings on FNAC must be assessed in the context of patient risk factors in determining the need for surgery. Indeterminate cytology may be present in 15% to 30% of FNA specimens and may require repeat FNAC. Lesions reported as atypia or a follicular lesion of undetermined significance are variably reported and have a 5% to 10% risk of malignancy. If a nonsurgical approach is taken, the nodule must be closely monitored, usually with US. Benign lesions are usually observed and require surgical removal only in cases of cosmetic or symptomatic concerns. These nodules must be aspirated again to confirm the diagnosis if growth is detected.

Molecular marker testing of indeterminate thyroid FNA specimens can also be used to aid decision making. More specifically, the purpose of molecular marker testing is ruling out or ruling in thyroid malignancy, based on the presence of certain mutations in the FNA specimen. As such, an ideal “rule-in” test would have a good positive predictive value for histopathologically proven malignancy, while a “rule-out” test would have a high negative predictive value. Currently, two popular molecular marker testing panels for indeterminate thyroid lesions are the Afirma Gene Expression Classifier and ThyroSeq, while ThyGenX/ThyraMIR and Rosetta GX Reveal have relatively less published clinical data. The Afirma Gene Expression Classifier has a high sensitivity (92%) and negative predictive value (93%), making it a good rule-out test. ThyroSeq also demonstrates a high negative predictive value (approximately 95%), making it another commonly used rule-out test. ThyGenX/ThyrMIR has the highest reported positive predictive value (~66%) of the commercially available genetic molecular tests, and therefore has been used as a rule-in test. The performance of these commercially available genetic molecular tests varies between studies and can be largely dependent upon the population studied with associated pre-test probability. The landscape of molecular genetic testing of thyroid nodules is rapidly changing, with frequent updates in clinical performance as companies work to modify and improve the performance of their commercially available products. Molecular genetic testing of indeterminate thyroid nodules will continue to remain an area of intense study in the coming years and use of molecular genetics in routine clinical decision-making will continue to be defined.

Review of Thyroid Neoplasms