Classification

The most common type of thyroid cancer is papillary thyroid cancer (PTC), representing 80% of all cases. The second most common type is follicular thyroid cancer (FTC), which represents 10% to 20% of all cases. Together, papillary and follicular cancers are termed differentiated thyroid cancer (DTC), and both arise from the thyroid follicular cells. Medullary thyroid cancer (MTC) comes from the parafollicular C cells. This neuroendocrine thyroid tumor represents 5% to 10% of all thyroid cancer cases and occurs in familial and sporadic forms. Finally, anaplastic thyroid cancer is one of the most aggressive and rapidly fatal cancers. It can develop from DTC that dedifferentiates over time or it also arises de novo.1,2,6,7 The first part of this section on thyroid cancer considers DTC, and the second part reviews MTC (Table 71-1, Fig. 71-1).

Etiology

External radiation exposure to the cervical region is one of the most well-known causes of thyroid cancer. Historically, patients received radiation treatments for enlarged tonsils or facial acne. Today, patients with cancer such as Hodgkin disease might still receive radiation treatments. In addition, children exposed to radioactive fallout from the Chernobyl (Russia) accident have demonstrated an increased incidence of thyroid cancer.8,9 Based on evidence from patients radiated for Hodgkin disease, doses of 40 Gy are potentially carcinogenic.¹⁰ Epidemiological studies report that 7% to 9% of patients who received 5 to 10 Gy external beam radiation develop thyroid cancer.¹¹ A lag time of 10 to 20 years usually exists between exposure and diagnosis of thyroid cancer, although much shorter periods have been reported (Table 71-2).¹¹

Another environmental etiology for thyroid cancer is dietary iodine content. A higher incidence of PTC exists in regions with high dietary iodine content, such as the Pacific rim and Iceland.¹² Iodine-deficient countries, in contrast, experience a higher incidence of FTC in addition to benign thyroid goiters. Many factors confound these studies that link changes in DTC rates to iodine intake. Ethnicity, selenium, goitrogen, and carcinogen intake likely play causative roles.¹³

Increasing investigation into molecular markers that can distinguish carcinoma from benign nodules has led to a greater understanding of the genetic alterations in thyroid cancer. For example, 70% of cancers found in Chernobyl survivors carried a RET and PTC gene (RET/PTC) rearrangement. The fusion of the tyrosine kinase encoding domain of the RET protein with a heterologous group of genes occurs in 20% to 40% cases of PTC and is called the RET/PTC rearrangement.¹⁴ RET/PTC rearrangements are frequent in small, multifocal PTCs accompanied by an inflammatory infiltrate, often seen in individuals exposed to ionizing radiation and in children.¹⁵ BRAF is a member of the RAF-MEK-ERK serine/threonine kinase-signaling cascade, and a BRAF mutation is found in 40% of PTC cases.¹⁶ The V600E BRAF point mutation or mutations in another member of this signaling pathway, RAS, are frequent in cases of poorly differentiated PTC or anaplastic thyroid cancer (ATC).¹⁷ Most BRAF substitutions keep the protein in a catalytically active form, resulting in constitutive activation of the RAF-MEK-ERK signaling cascade and constant mitogenic activity.

The Ras proteins are plasma membrane guanosine triphosphatases activated by growth factor receptors. Mutations that result in their constitutive activation lead to oncogenesis. RAS mutations also occur in 20% to 50% of follicular cancers. Similar to the RET/PTC rearrangement, another interchromosomal translocation occurs in FTC. The promoter element of the gene encoding paired box 8 (PAX8) fuses with the coding sequence of the peroxisome proliferator-activated receptor γ (PPARγ) gene in 35% of FTCs.19–19 The functional consequences of the PAX8-PPARγ rearrangement remain unclear. RAS mutations are also highly prevalent in FTC, but Nikiforova et al. found that RAS and PAX8-PPARγ rearrangements are mutually exclusive, suggesting that these are two distinct molecular pathways for FTC development.¹⁷

Aside from these acquired genetic lesions, some forms of DTC are also inherited. DTC is seen in familial syndromes such as Gardner syndrome, Cowden syndrome, and Werner syndrome.20,21 Familial nonmedullary thyroid cancer (FNMTC), defined as when two or more first-degree relatives are diagnosed with DTC in the absence of another syndrome, exhibits autosomal-dominant behavior with incomplete penetrance and variable expressivity.^23–23 Linkage analyses have identified several candidate genes for FNMTC, including TCO1, MNG1, fPTC/PRN, and NMTC1, but a single responsible gene has not been identified.^24–27 Compared to sporadic DTC, FNMTC is more aggressive with increased recurrence, local invasion, multicentricity, and lymph node metastases. However, in the absence of a suitable genetic test, families cannot be screened, and FNMTC is difficult to distinguish from sporadic DTC.²⁸

Classification and Prognosis

DTCs are divided broadly as papillary or follicular. Follicular variant PTC has features of both PTC and FTC, but is classified as a PTC subtype (see Table 71-1 and Fig. 71-1A). In general, well-differentiated PTC has an excellent prognosis with 5-year survival greater than 97%.⁴ Smaller tumors carry a better prognosis than larger tumors. PTC less than 1 cm in size are called papillary microcarcinomas, and have been reported in 10% to 30% of autopsy studies.^31–31 In the past, these tumors were incidentally detected in thyroidectomy specimens, but they are now detected with increasing frequency by high-resolution ultrasound. They are believed to have an excellent prognosis, but some may behave more aggressively than previously appreciated, and management remains controversial.^32,33

Age is another important determinant of prognosis in DTC. Older patients tend to have more poorly differentiated, aggressive variants. In these cases, death results from local invasion and extensive metastases. Therefore, the completeness of resection and extrathyroidal extension are two prognostic indicators employed in many staging systems for DTC.34,35

The role of lymph node metastases in determining DTC-specific survival remains controversial. Lymph node involvement is common in PTC, but the exact incidence of lymph node metastases depends on how it is defined. Palpable disease in the lymph nodes is present in 5% to 10% of patients with PTC, but ultrasound detects pathological lymph nodes in 30% of patients. Only 2% of patients with FTC have lymph node metastases since the route of spread is mostly hematogenous, but treatment guidelines and retrospective studies frequently consider PTC and FTC together. Routine histologic examination of lymph nodes detects DTC in 20% to 50% of patients, but when more detailed inspection is performed, up to 90% of patients with DTC will have lymph nodes with microscopic disease. Historically, lymph node involvement was felt to increase local recurrence without affecting survival, and therefore surgeons took a conservative approach to lymph node dissection for DTC. Wada et al. demonstrated that patients with pathologically positive lymph nodes had a recurrence rate of 16.3% compared to 0% in patients without pathological lymph nodes.³⁶ Whether metastatic lymph nodes are evident preoperatively appears to be an important factor determining recurrence. For example, Ito et al. found that if metastatic lymph nodes were not seen preoperatively, then the risk of nodal recurrence was only 1.5%. Of note, in this study of 590 patients with microcarcinomas, 40% of patients had lateral neck lymph node metastases identified histologically after prophylactic neck dissection.³⁷ Hence, lymph node metastases do affect recurrence, and clinically apparent nodes are more important than pathologically positive nodes. The impact of lymph nodes on survival is less clear. Large series and population-based studies suggest that there is a small, but significant, effect on survival.^38,39

Because of their questionable effect on mortality, lymph node status is not included in all of the staging systems available for DTC. For example, the AGES system considers age, grade, extrathyroidal extension, and size.⁴⁰ The AMES system uses age, distant (non-lymph node) metastases, extent of primary tumor, and size.⁴¹ Some, like the MACIS (metastases, age, complete excision, invasion, and size) system also account for the adequacy of surgical treatment.⁴² Alternatively, staging systems developed by the Ohio State University,⁴³ the European Organization for Research and Treatment of Cancer (EORTC),⁴⁴ the National Thyroid Cancer Treatment Cooperative Study (NTCTCS),⁴⁵ and the American Joint Committee on Cancer (AJCC)⁴⁶ all do consider lymph node status. The AJCC staging system is the most widely used (Table 71-3). It is also known as the TNM system because it considers tumor size (T), lymph node metastases (N), and distant metastases (M). Like many of the other thyroid cancer staging systems, it also considers age, with two different classifications for those younger and older than 45 years of age. In those younger than 45 years of age, patients with lymph node metastases are classified as stage I unless they have distant metastases (stage II) (Table 71-4).⁴⁶