Thyroid cancer was expected to have an annual incidence in the United States of 37,340 cases in 2008 and has become the sixth most common cancer in women.1 There has been a 2.4-fold increase in the incidence of thyroid cancer in the United States over the past 30 years, from 3.6 per 100,000 in 1973 to 8.7 per 100,000 in 2003, with virtually the entire increase attributable to the papillary type, particularly cancers smaller than 2 cm in diameter.2

Papillary thyroid cancer (PTC), which is a differentiated type of thyroid cancer derived from follicular epithelial cells, is the most common histologic type of thyroid cancer, occurring in about 80% of cases.3 Multiple subtypes of PTC have been described and include the classical form that contains areas of a predominantly papillary growth pattern as well as follicles; a follicular variant of PTC (FVPTC) that grows in a follicular pattern; and more aggressive variants, including the tall cell, columnar cell, diffuse sclerosing, and insular variants of PTC.4

Both genetic and environmental factors may increase the risk of developing PTC. About 3% of cases of PTC are familial.5 Some familial syndromes known to be associated with PTC include familial adenomatous polyposis (FAP) and its variant, Gardner syndrome (both caused by a mutation in the APC gene); Cowden syndrome (also known as multiple hamartoma syndrome; caused by a mutation in the PTEN gene); and Carney complex (caused by a mutation in the PRKAR1A gene).6,7 A family history of PTC in two first-degree relatives increases the risk of PTC three- to nine-fold, and these families are likely part of a familial nonmedullary thyroid cancer (FNMTC) kindred, whose specific genetic defect has not yet been determined.8

The strongest evidence linking thyroid cancer to an environmental cause exists for exposure to ionizing radiation.9 These data are derived from studies of children who were exposed to the nuclear fallout from Chernobyl, adult survivors of the atomic bombings of Hiroshima and Nagasaki, and patients who received head and neck radiotherapy in childhood for the treatment of a variety of benign conditions such as enlarged tonsils, tinea capitis, acne, or an enlarged thymus.

Other factors that have been investigated to determine their impact on the risk of developing thyroid cancer include hormonal factors, iodine intake, and the presence of Hashimoto’s thyroiditis. Even though the majority of patients with PTC are women, no convincing hormonal associations have been elucidated.10 Studies examining the influence of iodine intake on the risk of thyroid cancer have shown conflicting results, and at the present time, iodine intake is generally not considered to affect a patient’s risk of developing thyroid cancer.11 The influence of Hashimoto’s thyroiditis on thyroid cancer risk is controversial, but large studies have shown an increased prevalence of Hashimoto’s thyroiditis in patients with PTC.12,13

PTC is more common in women than men by a ratio of approximately 3:1 and has a median age of diagnosis of 45 years.1,14 Patients with PTC are usually asymptomatic and present with a solitary thyroid nodule or with a gland that contains multiple thyroid nodules. These nodules are usually palpated on routine physical examination or discovered during an imaging study done for another reason. Some patients present with a palpable cervical lymph node. Occasionally, a patient presents with symptoms worrisome for an aggressive or invasive thyroid cancer such as hoarseness, dysphagia, or hemoptysis. In contrast, many PTCs incidentally discovered during the pathologic examination of a thyroid gland after surgery for benign disease, are usually less than 1 cm in diameter, and are termed papillary microcarcinomas. Even when patients present with cervical lymph node metastases or invasion into surrounding neck structures, PTC is largely a localized disease; distant metastases are uncommon, occurring in fewer than 4% of patients at the time of initial diagnosis.15

The prognosis of PTC is excellent, with an overall 20- to 25-year cancer-specific mortality rate of 5%.16 Some patients, however, have a worse prognosis than others, and multiple prognostic scoring systems have been promulgated since the late 1970s in an attempt to distinguish patients at low versus high risk of death from thyroid cancer. The most well-known scoring systems include AGES (age, grade, extent, size), AMES (age, metastasis, extent, size); MACIS (metastasis, age, completeness of resection, invasion, size); and the EORTC (European Organization for Research and Treatment of Cancer) score, which takes into account gender, histology, invasion, and metastasis. For the most part, all of these scoring systems have been replaced by the American Joint Committee on Cancer’s TNM (tumor, node, metastasis) system, which is based on the size and extent of the primary tumor (extrathyroidal extension will upstage the T stage), lymph node involvement, and the presence of distant metastasis.17 Regardless of the classification scheme used, most patients with PTC (~80%) fall into a low-risk group, with 10-year cancer-specific survival rates of 97% to 100%.16,18,19

In contrast to staging systems for other cancers, most of those for PTC take into account the patient’s age, which has been found to influence prognosis. In the TNM system, patients younger than 45 years are classified as having stage I or II disease, with only the presence of distant metastases distinguishing the two. It is imperative to note that patients in this age group who have lymph node metastases are still classified as having stage I disease. Patients who are age 45 years or older are categorized into having stage I, II, II, or IV disease depending on tumor size or invasion as well as lymph node or distant metastases.

In addition to the prognostic factors examined in these staging systems, other factors such as histologic subtype of PTC, as well as genetic factors, have been associated with a worse prognosis. The tall cell, columnar cell, diffuse sclerosing, and insular histologic variants of PTC, as well as PTCs that contain a mutation in the gene for the B-type isoform of RAF kinase (BRAF), are considered more aggressive.4,20

The diagnostic investigation of a patient with PTC usually begins with the evaluation of a thyroid nodule, which includes ultrasonography of the thyroid gland and measurement of serum thyroid-stimulating hormone (TSH) level. A diagnosis of PTC is usually made by fine-needle aspiration (FNA) biopsy. Although most patients with thyroid cancer are euthyroid, higher TSH concentrations, even within the normal range, may be associated with an increased risk of cancer in a thyroid nodule.21

After a diagnosis of thyroid cancer has been established, the patient should then undergo preoperative staging (Figure 4-1). Because the pattern of spread of PTC is usually lymphatogenous, ultrasound examination of the cervical lymph nodes may help determine the extent of disease. Studies have shown that routine preoperative ultrasonography can detect nonpalpable lymph node metastases in 14% to 20% of patients, which then changes the planned initial operation.22,23 In addition, ultrasonography may demonstrate the patency of the internal jugular veins. The guidelines of the American Thyroid Association (ATA) and American Association of Clinical Endocrinologists both recommend the routine use of preoperative neck ultrasonography to evaluate the cervical lymph nodes in patients with a diagnosis of PTC,24,25 but the guidelines of the National Comprehensive Cancer Network (NCCN) recommend only consideration of this test.7 If a suspicious-appearing lymph node is detected by ultrasonography, FNA biopsy should be performed.

Other diagnostic tests should be tailored to the clinical assessment of how aggressive or invasive the thyroid cancer is suspected to be (see Figure 4-1). Features that should increase the preoperative suspicion of an aggressive or invasive thyroid cancer include rapid growth of the tumor, fixation to surrounding structures, symptoms of invasion into surrounding neck structures (e.g., hoarseness or hemoptysis), occluded internal jugular veins, and palpable cervical lymphadenopathy. In these patients, other cross-sectional imaging tests such as computed tomography (CT) or magnetic resonance imaging (MRI) may be helpful in determining the extent of the tumor and planning the extent of resection. Cross-sectional imaging studies are also useful when a substernal extension of the thyroid gland is present. It is important to note that CT imaging should be done without intravenous contrast because the administration of iodinated contrast agents may obviate the use of postoperative radioactive iodine (RAI) for several months. Other imaging, such as fluorodeoxyglucose positron emission tomography (FDG-PET) scanning, may be useful in patients with poorly differentiated PTC, who are at increased risk of distant metastases. The use of CT, MRI, and FDG-PET in the routine evaluation of patients with PTC, however, is not recommended.25

In addition to cross-sectional imaging, endoscopic examination via laryngoscopy, bronchoscopy, or esophagoscopy is recommended if there is a preoperative suspicion for invasion into the recurrent laryngeal nerve (RLN), trachea, or esophagus, respectively. The role of routine vocal cord examination in the evaluation of patients with PTC is controversial. Some experts recommend selective preoperative laryngoscopy only for symptomatic patients or for patients who have previously undergone a cervical operation because studies examining this issue have shown that most patients with a preoperatively identified RLN palsy were symptomatic, had previously undergone thyroid surgery, or had an invasive thyroid cancer.26–28 Others recommend routine laryngoscopy because patients with thyroid malignancies may have a “silent” (i.e., compensated) preoperative RLN palsy. Discovery of a preoperative RLN palsy suggests extrathyroidal extension of the tumor and may change the operative plan, and routine postoperative laryngoscopy allows surgeons to accurately analyze their RLN-related complication rates.

The management of patients with PTC consists of four main components: adequate surgical extirpation of disease, adjunctive RAI ablation in selected cases, TSH suppression, and surveillance. The overall management strategy for any individual patient depends on preoperative and intraoperative findings as well as the final TNM classification and postoperative evaluation (Figures 4-2 and 4-3).