The thyroid gland originates from both primitive pharyngeal and the neural crest cells. It is the first endocrine gland to develop in the human body. The medial portion of the gland derives from the endodermal diverticulum of the first and second pharyngeal pouches at the foramen cecum. It then descends to its pretracheal position along the midline neck during 4 to 7 weeks of gestation, and the proximal portion degenerates into a fibrous stalk. If any of these portions persists, a thyroglossal duct cyst (TGDC) may result. The distal portion gives rise to the pyramidal lobe. The lateral portion of the gland derives from the fourth and fifth pharyngeal pouches, which descend to fuse with the medial portion of the gland.

Parafollicular C cells originate from the ectoderm neural crest cells as the ultimobranchial body, which secretes calcitonin. In mammals, the ultimobranchial body and medial portion of the fourth pharyngeal fuse into the lateral lobes of the thyroid. Because of this, the majority of C cells are located deep within the upper one-third of the lateral lobe, the most common location for medullary thyroid carcinoma (MTC).

Ectopic thyroid tissue can be found anywhere along the course of its developmental descent in the midline anterior neck. Lingual thyroid can be found at its origin at the foremen cecum due to failure to descend. Seventy percent of the patients with lingual thyroids have no thyroid tissue in the neck. Thyroid function should be evaluated before the surgical removal of the lingual thyroid glands. A TGDC is the most common congenital midline cervical anomaly. It may develop at any location along the thyroglossal duct tract, most commonly at the midline upper cervical location close to the hyoid bone. Rarely, this entity can occur in a lateral position. The hyoid bone divides this tract into upper and lower segments. Thus, surgical management of the TGDC (Sistrunk procedure) should remove the middle segment of hyoid bone to prevent recurrence. Preoperative imaging will aid in delineating the nature of a midline mass as well as identifying functional thyroid tissue prior to complete TGDC excision. High-resolution ultrasound, CT, and MRI are commonly used in detecting TGDC. Calcification seen in a CT scanning raises suspicion of papillary carcinoma arising from TGDC.

Risk factors for thyroid cancer have been studied extensively. They include age of the patient, gender, history of previous radiation, family history, environmental exposures, and molecular genetic factors. It has been widely accepted that papillary thyroid carcinoma (PTC) is twice as common in women as in men (5). Young patients have a better prognosis than older patients. The clinical presentation differs significantly in terms of the size, extent of the cancer, the presence and the number of lymph node metastases, and response to the treatment (6). Indeed, AJCC has incorporated age as part of the staging criteria for differentiated thyroid cancer (DTC).

Although there is no clear association between dietary iodine supplementation and thyroid cancer, the pattern of thyroid cancer in iodine-sufficient areas differs significantly from iodine-deficient areas, with the shift from high proportion of follicular carcinoma to PTC (6,7).

It is well established that exposure to ionizing radiation to the head and neck region during childhood increases the risk of thyroid cancer. Radiation therapy (RT) was once a therapy for tonsil and adenoid hyperplasia, thymic enlargement, acne, hemangioma, and Hodgkin disease (mantle irradiation) to the head and neck. The risk of thyroid cancer often RT exposure is dose dependent and is greatest for children less than 15 years old. The 25-year follow-up after the Chernobyl accident demonstrated that children and adolescents exposed to radioiodine from the Chernobyl fallout have a substantial dose-related increase in thyroid cancer, with the risk greatest in those less than 18 years old at exposure (8). Fortunately, the disease-specific mortality rate in this patient population is quite low, at 1% or less (9). The increased incidence of thyroid cancer in those greater than 18 years old during the Chernobyl fallout is less definitive.

A patient with a family history of thyroid cancer has an increased risk to develop thyroid cancer, and 5% to 10% of all thyroid carcinoma cases are hereditary (10). Gardner syndrome and Peutz-Jeghers syndrome are both associated with PTC. Cowden disease is associated with follicular thyroid carcinoma (FTC). MEN IIA and MEN IIB are associated with family history of MTC (11).

The knowledge of molecular genetics and signaling pathways in thyroid cancer has expanded in recent years. Numerous molecular alterations in thyroid cancer have been identified, and are actively studied in clinical trials as therapeutic targets for recurrent disease. Among them, four major mutations involved in development of differentiated thyroid cancer (DTC), BRAF and RAS point mutation, RET (REarranged during Transfection)/PTC, and PAX8/peroxisome proliferator-activated receptor γ (PPARγ) rearrangements, seem to have most relevant clinical implications (12). Like many other malignancies, genetic alterations in the mitogen-activated protein kinase (MAPK) signaling pathway are involved in development of PTC (Fig. 133.1) (13).

PTC often carries mutually exclusive BRAF and RAS point mutations and RET/PTC rearrangements, which are activated in MAPK signaling pathway. Mutation in one of these genes presents in more than 70% of PTC (14,15,16). BRAF point mutations have been reported in 40% to 45% of PTC. BRAF V600E mutation has been found in 70% to 80% of tall-cell variant of PTC and 60% of classical PTC and strongly correlated with aggressive features of this disease including extrathyroidal extension (ECE), lymph node, or distant metastases (14,17,18). BRAF V600E is not found in FTC or other benign thyroid nodules, which makes it a specific tumor marker of PTC. This association has also been reported in papillary microcarcinomas, which might have some clinical implications in the management of these tumors (19). RET/PTC rearrangements are found in 20% of adult papillary carcinomas, most commonly in patients with history of radiation (20,21). It is common in patients with history of radiation and young adults with PTC. However, it has been found in other benign thyroid lesions or hyalinizing trabecular tumors (21,22). In MTC, RET is activated by point mutation rather than chromosomal rearrangement, as found in PTC. Point mutations of the RAS genes (HRAS, KRAS, and NRAS) are found in FTC, PTC, and follicular adenoma. In thyroid carcinoma, KRAS and NRAS are the most commonly altered. RAS mutations are found in 45% of follicular carcinoma and 10% papillary carcinoma (13). In the latter, PTC with RAS mutation is almost always of the follicular variant (12). These are also found in other follicular adenomas/hyperplasia or goiters. PAX8/PPARγ rearrangement is present in 35% of classic follicular carcinomas. RAS mutation and PAX8/PPARγ rearrangement are rarely overlapping. Mutations in the RAS genes or PAX8/PPARg rearrangement occur in approximately 70% of FTC (23).

Compelling data indicate that molecular testing of thyroid FNA specimens may significantly improve the accuracy of preoperative cytologic diagnosis of thyroid nodules, especially in the subgroups including follicular lesion of indeterminate significance (FLUS), follicular neoplasm, and suspicious for malignancy. Current ATA guidelines recommend that the molecular test results may be considered for indeterminate FNA cytology to help guide the management of those patients. The feasibility and diagnostic utility of molecular testing in FNA of thyroid nodules has been reported in a recent large prospective study including 470 FNA samples. Molecular testing demonstrated 100% accuracy for malignancy in all mutation-positive FLUS cases (24). BRAF was the most common mutation and had 100% positive predictive value (PPV) for PTC, whereas RAS mutation confers 87.5% probability of malignancy (24). In light of the finding in this study, the patients with
mutation-positive and cytologic indeterminate nodules are considered for total thyroidectomy, especially with BRAF mutations, to reduce the need for intraoperative pathologic consultation and to avoid a second surgery. In addition to the diagnostic value of molecular testing, the aggressive behavior of BRAF-positive PTCs provides prognostic information to refine patients’ management, including consideration of central neck dissection. Although still early in clinical application, the expanding knowledge of thyroid tumor biology has started translating into clinical practice, and molecular testing in thyroid FNA will be a valuable tool for diagnosis and better prognostication of thyroid cancer.

Most commonly thyroid neoplasms present as either palpable thyroid nodules or nonpalpable nodules incidentally found by imaging studies, so-called incidentalomas. These “incidentalomas” carry the same risk of malignancy as palpable nodules with the same size. Generally, any nodule greater than 1 cm warrants evaluation. Occasionally, subcentimeter nodules with worrisome ultrasound features, previous history of head and neck irradiation, family history of thyroid cancer, or associated neck lymphadenopathy require further evaluation. Recent studies demonstrated 27% to 42% risk of malignancy in focal or unilateral uptake in ¹⁸FDG-PET scan (25,26,27). The term “PAINs” (PET-Associated Incidental Neoplasm) was introduced, and the prompt evaluation and treatment of these patients are warranted (28).