CHAPTER 48: THYROID CANCER

The various types of benign thyroid nodules are listed in Table 48-1. These lesions are common (5–10% adults), particularly when assessed by sensitive techniques such as ultrasound. The risk of malignancy is very low for macrofollicular adenomas and normofollicular adenomas. Microfollicular, trabecular, and Hürthle cell variants raise greater concern, and the histology is more difficult to interpret. About one-third of palpable nodules are thyroid cysts. These may be recognized by their ultrasound appearance or based on aspiration of large amounts of pink or straw-colored fluid (colloid). Many are mixed cystic and solid lesions, in which case it is desirable to aspirate cellular components under ultrasound or harvest cells after cytospin of cyst fluid. Cysts frequently recur, even after repeated aspiration, and may require surgical excision if they are large or if the cytology is suspicious. Sclerosis has been used with variable success but is often painful and may be complicated by infiltration of the sclerosing agent.

The treatment approach for benign nodules is similar to that for multinodular goitermultinodular goiter (MNG). TSH suppression with levothyroxine decreases the size of about 30% of nodules and may prevent further growth. If a nodule has not decreased in size after 6–12 months of suppressive therapy, treatment should be discontinued because little benefit is likely to accrue from long-term treatment; the risk of iatrogenic subclinical thyrotoxicosis should also be considered.

Thyroid carcinoma is the most common malignancy of the endocrine system. Malignant tumors derived from the follicular epithelium are classified according to histologic features. Differentiated tumors, such as PTC or follicular thyroid cancer (FTC), are often curable, and the prognosis is good for patients identified with early-stage disease. In contrast, anaplastic thyroid cancer (ATC) is aggressive, responds poorly to treatment, and is associated with a bleak prognosis.

The incidence of thyroid cancer (~9/100,000 per year) increases with age, plateauing after about age 50 years (Fig. 48-2). Age is also an important prognostic factor—thyroid cancer at a young age (<20 years) or in older persons (>45 years) is associated with a worse prognosis. Thyroid cancer is twice as common in women as men, but male gender is associated with a worse prognosis. Additional important risk factors include a history of childhood head or neck irradiation, large nodule size (≥4 cm), evidence for local tumor fixation or invasion into lymph nodes, and the presence of metastases (Table 48-2). Several unique features of thyroid cancer facilitate its management: (1) thyroid nodules are readily palpable, allowing early detection and biopsy by FNA; (2) iodine radioisotopes can be used to diagnose (¹²³I) and treat (¹³¹I) differentiated thyroid cancer, reflecting the unique uptake of this anion by the thyroid gland; and (3) serum markers allow the detection of residual or recurrent disease, including the use of thyroglobulin (Tg) levels for PTC and FTC and calcitonin for medullary thyroid cancer (MTC).

Thyroid neoplasms can arise in each of the cell types that populate the gland, including thyroid follicular cells, calcitonin-producing C cells, lymphocytes, and stromal and vascular elements, as well as metastases from other sites (Table 48-1). The American Joint Committee on Cancer (AJCC) has designated a staging system using the TNM (tumor, node, metastasis) classification (Table 48-3). Several other classification and staging systems are also widely used, some of which place greater emphasis on histologic features or risk factors such as age or gender.

RADIATION

Early studies of the pathogenesis of thyroid cancer focused on the role of external radiation, which predisposes to chromosomal breaks, leading to genetic rearrangements and loss of tumor-suppressor genes. External radiation of the mediastinum, face, head, and neck region was administered in the past to treat an array of conditions, including acne and enlargement of the thymus, tonsils, and adenoids. Radiation exposure increases the risk of benign and malignant thyroid nodules, is associated with multicentric cancers, and shifts the incidence of thyroid cancer to an earlier age group. Radiation from nuclear fallout also increases the risk of thyroid cancer. Children seem more predisposed to the effects of radiation than adults. Of note, radiation derived from ¹³¹I therapy appears to contribute minimal increased risk of thyroid cancer.

THYROID-STIMULATING HORMONE AND GROWTH FACTORS

Many differentiated thyroid cancers express TSH receptors and, therefore, remain responsive to TSH. This observation provides the rationale for levothyroxine (T₄) suppression of TSH in patients with thyroid cancer. Residual expression of TSH receptors also allows TSH-stimulated uptake of ¹³¹I therapy (see later discussion).

ONCOGENES AND TUMOR-SUPPRESSOR GENES

Thyroid cancers are monoclonal in origin, consistent with the idea that they originate as a consequence of mutations that confer a growth advantage to a single cell. In addition to increased rates of proliferation, some thyroid cancers exhibit impaired apoptosis and features that enhance invasion, angiogenesis, and metastasis. Thyroid neoplasms have been analyzed for a variety of genetic alterations but without clear evidence of an ordered acquisition of somatic mutations as they progress from the benign to the malignant state. On the other hand, certain mutations are relatively specific for thyroid neoplasia, some of which correlate with histologic classification (Table 48-4).

As described earlier, activating mutations of the TSH-R and the G_Sα subunit are associated with autonomously functioning nodules. Though these mutations induce thyroid cell growth, this type of nodule is almost always benign.

Activation of the RET-RAS-BRAF signaling pathway is seen in most PTCs, though the types of mutations are heterogeneous. A variety of rearrangements involving the RET gene on chromosome 10 brings this receptor tyrosine kinase under the control of other promoters, leading to receptor overexpression. RET rearrangements occur in 20–40% of PTCs in different series and were observed with increased frequency in tumors developing after the Chernobyl radiation accident. Rearrangements in PTC have also been observed for another tyrosine kinase gene, TRK1, which is located on chromosome 1. To date, the identification of PTC with RET or TRK1 rearrangements has not proven useful for predicting prognosis or treatment responses. BRAF mutations appear to be the most common genetic alteration in PTC. These mutations activate the kinase, which stimulates the mitogen-activated protein MAP kinase (MAPK) cascade. RAS mutations, which also stimulate the MAPK cascade, are found in about 20–30% of thyroid neoplasms, including both PTC and FTC. Of note, simultaneous RET, BRAF, and RAS mutations do not occur in the same tumor, suggesting that activation of the MAPK cascade is critical for tumor development, independent of the step that initiates the cascade.

RAS mutations also occur in FTCs. In addition, a rearrangement of the thyroid developmental transcription factor PAX8 with the nuclear receptor PPARγ is identified in a significant fraction of FTCs. Loss of heterozygosity of 3p or 11q, consistent with deletions of tumor-suppressor genes, is also common in FTCs.

Most of the mutations seen in differentiated thyroid cancers have also been detected in ATCs. BRAF mutations are seen in up to 50% of ATCs. Mutations in CTNNB1, which encodes β-catenin, occur in about two-thirds of ATCs, but not in PTC or FTC. Mutations of the tumor suppressor p53 also play an important role in the development of ATC. Because p53 plays a role in cell cycle surveillance, DNA repair, and apoptosis, its loss may contribute to the rapid acquisition of genetic instability as well as poor treatment responses (Chap. 25) (Table 48-4).

The role of molecular diagnostics in the clinical management of thyroid cancer is under investigation. In principle, analyses of specific mutations might aid in classification, prognosis, or choice of treatment. However, there is no clear evidence to date that this information alters clinical decision making.

MTC, when associated with multiple endocrine neoplasia (MEN) type 2, harbors an inherited mutation of the RET gene. Unlike the rearrangements of RET seen in PTC, the mutations in MEN2 are point mutations that induce constitutive activity of the tyrosine kinase (Chap. 50). MTC is preceded by hyperplasia of the C cells, raising the likelihood that as-yet-unidentified "second hits" lead to cellular transformation. A subset of sporadic MTC contain somatic mutations that activate RET.

PAPILLARY

PTC is the most common type of thyroid cancer, accounting for 70–90% of well-differentiated thyroid malignancies. Microscopic PTC is present in up to 25% of thyroid glands at autopsy, but most of these lesions are very small (several millimeters) and are not clinically significant. Characteristic cytologic features of PTC help make the diagnosis by FNA or after surgical resection; these include psammoma bodies, cleaved nuclei with an "orphan-Annie" appearance caused by large nucleoli, and the formation of papillary structures.

PTC tends to be multifocal and to invade locally within the thyroid gland as well as through the thyroid capsule and into adjacent structures in the neck. It has a propensity to spread via the lymphatic system but can metastasize hematogenously as well, particularly to bone and lung. Because of the relatively slow growth of the tumor, a significant burden of pulmonary metastases may accumulate, sometimes with remarkably few symptoms. The prognostic implication of lymph node spread is debated. Lymph node involvement by thyroid cancer can be well tolerated but appears to increase the risk of recurrence and mortality, particularly in older patients. The staging of PTC by the TNM system is outlined in Table 48-3. Most papillary cancers are identified in the early stages (>80% stages I or II) and have an excellent prognosis, with survival curves similar to expected survival (Fig. 48-3A). Mortality is markedly increased in stage IV disease (distant metastases), but this group comprises only about 1% of patients. The treatment of PTC is described later.

FOLLICULAR

The incidence of FTC varies widely in different parts of the world; it is more common in iodine-deficient regions. FTC is difficult to diagnose by FNA because the distinction between benign and malignant follicular neoplasms rests largely on evidence of invasion into vessels, nerves, or adjacent structures. FTC tends to spread by hematogenous routes leading to bone, lung, and central nervous system metastases. Mortality rates associated with FTC are less favorable than for PTC, in part because a larger proportion of patients present with stage IV disease (Fig. 48-3B). Poor prognostic features include distant metastases, age >50 years, primary tumor size >4 cm, Hürthle cell histology, and the presence of marked vascular invasion.

ANAPLASTIC THYROID CANCER

As noted earlier, ATC is a poorly differentiated and aggressive cancer. The prognosis is poor, and most patients die within 6 months of diagnosis. Because of the undifferentiated state of these tumors, the uptake of radioiodine is usually negligible, but it can be used therapeutically if there is residual uptake. Chemotherapy has been attempted with multiple agents, including anthracyclines and paclitaxel, but it is usually ineffective. External-beam radiation therapy can be attempted and continued if tumors are responsive.

THYROID LYMPHOMA

Lymphoma in the thyroid gland often arises in the background of Hashimoto's thyroiditis. A rapidly expanding thyroid mass suggests the possibility of this diagnosis. Diffuse large-cell lymphoma is the most common type in the thyroid. Biopsies reveal sheets of lymphoid cells that can be difficult to distinguish from small cell lung cancer or ATC. These tumors are often highly sensitive to external radiation. Surgical resection should be avoided as initial therapy because it may spread disease that is otherwise localized to the thyroid. If staging indicates disease outside of the thyroid, treatment should follow guidelines used for other forms of lymphoma (Chap. 15).

MTC can be sporadic or familial and accounts for about 5% of thyroid cancers. There are three familial forms of MTC: MEN 2A, MEN 2B, and familial MTC without other features of MEN (Chap. 50). In general, MTC is more aggressive in MEN 2B than in MEN 2A, and familial MTC is more aggressive than sporadic MTC. Elevated serum calcitonin provides a marker of residual or recurrent disease. It is reasonable to test all patients with MTC for RET mutations, as genetic counseling and testing of family members can be offered to those individuals who test positive for mutations.

The management of MTC is primarily surgical. Unlike tumors derived from thyroid follicular cells, these tumors do not take up radioiodine. External radiation treatment and chemotherapy may provide palliation in patients with advanced disease (Chap. 50).