Evaluation of Thyroid Nodules

David M. Slovik

Thyroid nodules are extremely common, both clinically and on imaging studies of the neck. A palpable thyroid nodule can be detected in 4% to 7% of the adult population (10 to 20 million people in the United States). The prevalence of nodules in autopsy series approaches 50%, a figure that is approximated by patients undergoing modern high-resolution, real-time ultrasonography of the thyroid. The incidence of thyroid nodules increases with age and head or neck irradiation; it is more common in women than in men. In patients with thyroid nodules, the rate of carcinoma is twice as high in men than women and highest in those older than age 60 years or younger than age 30 years.

The principal objective in evaluating thyroid nodules is to differentiate malignant from benign lesions. Most thyroid nodules are benign. About 70% of nodules subjected to fine needle biopsy prove to be benign; 4% to 5% are malignant; in the remainder, the cytologic findings are either inadequate or indeterminate. Additional tasks are to determine the functional status of a nodule and assess any adverse effect on neighboring structures.

Because of the high frequency and potential importance of thyroid nodules, the primary care physician must be able to coordinate a cost-effective evaluation. To that end, familiarity with the indications for and utilities of ultrasonography, fine needle aspiration (FNA), and radionuclide scanning is necessary, as well as an appreciation for the emerging use of geneexpression testing. Understanding the respective roles of thyroidectomy, suppressive therapy, and watchful waiting facilitates the formulation of an appropriate program of management.

PATHOPHYSIOLOGY AND CLINICAL PRESENTATION (1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13 and 14)

Thyroid nodules may be single or multiple, with or without underlying disturbances of hormonal homeostasis. A solitary nodule is usually the more worrisome because it may represent a malignancy, although on occasion a multinodular gland may harbor a cancer, especially if there is a dominant nodule. Thyroid nodules are usually asymptomatic and discovered by the patient or examining physician or incidentally as a consequence of a neck imaging procedure and referred to as a “thyroid incidentaloma.” Nonpalpable nodules have the same risk as palpable nodules of the same size. Large nodules may cause a cosmetic problem or compress an adjacent structure. Thyroid nodules are usually painless unless rapid growth, inflammation, or hemorrhage occurs, and they may then produce significant discomfort.

Solitary Nodule

Solitary thyroid nodules represent benign adenomas, carcinomas, or multinodular conditions in which only a single nodule is palpable.

Benign Adenomas

Benign adenomas account for most nonmalignant, truly solitary nodules. The majority, designated as follicular (macrofollicular or microfollicular), have a fibrous capsule and a histologic appearance characteristic of thyroid tissue; the remainder, labeled colloid or adenomatous nodules, are not well-encapsulated and are usually found in a multinodular goiter. They behave similarly. Growth is typically slow, extending over many years. Follicular adenomas rarely become large enough to encroach on the trachea or esophagus. Thyroid adenomas are usually monoclonal in origin. Thyroid-stimulating hormone (TSH) receptors are present in most, making them hormonally responsive. Most do not produce much thyroid hormone, and their limited radioiodine uptake on scan sometimes gives the appearance of a “cold” nodule, suggesting malignancy. Microfollicular or cellular adenomas differ from follicular carcinoma by their lack of capsular invasion; they are usually excised to exclude cancer unless they show autonomous function on thyroid scintigraphy.

A few follicular adenomas produce such large quantities of thyroid hormone that the patient presents with thyrotoxicosis (see Chapter 103). This is particularly true of so-called “toxic” adenomas exceeding 3 cm in diameter. They function autonomously, suppress TSH (which renders the rest of the gland atrophic), and appear as hot nodules on thyroid scan. Patients with a smaller hot nodule may remain euthyroid, although enough thyroid hormone is produced to suppress the rest of the gland and render it atrophic.

Benign adenomas that outgrow their blood supply may undergo necrosis, degenerate, become filled with fluid, and appear on ultrasonography as nodules with solid and cystic elements. Adenomas make up a significant proportion of such “cystic” lesions.

Thyroid Carcinomas

Thyroid carcinomas are uncommon; they account for approximately 1% of all malignant neoplasia. The current incidence is 5 to 10 per 100,000 persons annually, although it is higher in areas with radiation exposure. They are more frequent in women than in men (3:1). The prevalence is higher in children, adults younger than 30 years or older than 60 years, and patients with a history of prior head or neck irradiation or a family history of thyroid cancer. On radioiodine scan, most thyroid carcinomas present as cold nodules, failing to take up iodine, although on technetium scan, a rare malignant nodule will take up the radionuclide. On ultrasonography, most cancers are solid, although a mixed cystic-solid appearance is encountered in about 20%, and even a purely cystic-appearing lesion may occasionally be malignant.

Papillary and Mixed Papillary-Follicular Carcinomas.

Papillary and mixed papillary-follicular carcinomas are the most common and account for 70% of all thyroid malignancies. Up to 15% to 20% of all autopsies show microscopic foci of papillary carcinoma. The natural history of microcarcinoma is uncertain. A tumor that contains any papillary element is considered papillary even if it contains follicular components. The lesions tend to be very slow growing, spreading locally to adjacent cervical lymph nodes but not metastasizing distantly until very late and then in only 5% of cases. Consequently, the prognosis is good even after local spread has occurred. Although most are solid, some may present as mixed cystic-solid lesions because of necrosis and liquefaction.

Follicular Carcinomas.

Follicular carcinomas, which make up another 10% to 20% of thyroid cancers, are also slow growing. Local spread to regional nodes may occur without invasion of the thyroid capsule, but this does not alter the prognosis. Hematogenous spread can develop early, and the initial presentation is often a metastasis to the lung or bone. Follicular carcinomas represent a wide spectrum of disease. Prognosis depends on the degree of vascular invasion and metastases.

Anaplastic Carcinomas.

Anaplastic carcinomas make up another 10% to 12% of cases. These show a high degree of cellular undifferentiation and are among the most aggressive of human cancers, being very invasive, usually inoperable, and fatal within 1 year. They often present as a rapidly growing thyroid mass, with hoarseness, dyspnea, and dysphagia.

Medullary Carcinomas.

Medullary carcinomas, derived from the parafollicular cells of the thyroid, represent 10% of thyroid cancers. Sporadic and familial forms of the disease are seen; among the latter are familial medullary cancers unaccompanied by other conditions and multiple endocrine neoplasia (MEN) types IIA and IIB (which occur in conjunction with pheochromocytoma and hyperparathyroidism). Mutations in the HRPT2 gene have been found with sporadic disease, and mutations in the RET protooncogene have been strongly associated with familial medullary thyroid carcinoma and MEN 2A and 2B. Timing of malignant transformation and clinical onset of hereditary forms varies by specific mutation. The malignancy often presents as a nodule located in the upper half of the thyroid gland. It can be multicentric, especially in the familial forms. Approximately 70% of medullary carcinomas of the thyroid occur sporadically. Calcitonin, produced by the parafollicular or “C” cells, is a unique tumor marker for medullary carcinoma, yet these patients remain eucalcemic.

The prognosis is highly variable but similar to that of follicular carcinoma. Tumor spread is often to the lymph nodes of the neck and mediastinum, but distant spread to the lungs, bone, and liver may also occur.

Lymphoma.

Lymphoma may sometimes develop as a primary lesion within the thyroid; it makes up 1% to 4% of thyroid malignancies. Up to 70% arise in patients with chronic lymphocytic thyroiditis. Its clinical course is a function of tissue type and stage at time of presentation (see Chapter 84). Spread to local nodes is common and prominent.

Metastatic Carcinoma.

Metastatic carcinoma to the thyroid primarily from renal, breast, and lung cancer is uncommon but can occur.

Multiple Nodules

Thyroid glands containing multiple nodules are most often a consequence of Hashimoto thyroiditis and less often due to multinodular goiter. Thyroid cancers rarely arise in a multinodular gland.

Hashimoto Thyroiditis

Hashimoto thyroiditis, an autoimmune condition, is the leading cause of a multinodular gland in the United States. Evidence of the condition can be found in about 4% of the general population and up to 15% of women older than the age of 65 years. Women patients outnumber men by a ratio of 3:1. Pathologically, there is a marked lymphocytic infiltration, formation of germinal centers, atrophy of thyroid follicles, absent colloid, fibrosis, and oxyphilic or eosinophilic changes involving follicular epithelial cells. Although not unique to this condition, antithyroid antibodies are found in 70% to 95% of patients, consisting of thyroid peroxidase antibody and thyroglobulin antibody. Peroxidase antibodies are also found in Graves disease and thyroglobulin antibodies, in thyroid cancer.

About one third of Hashimoto patients manifest a multinodular goiter, although euthyroid goiter is actually the most common presentation. The immunologically-mediated injury impairs thyroxine synthesis and increases leakage of hormone into the circulation. One third of patients experience progressive loss of glandular function and eventually become hypothyroid. Hyperthyroidism is uncommon but can occur in patients with a prominent lymphocytic infiltrate.

Multinodular Goiter

Multinodular goiter is the second most common cause of a multinodular gland in adults. It represents an advanced stage of focal autonomous hyperplasia, which initially presents as a diffusely enlarged gland but then progresses to multinodularity as areas of focal hyperplasia undergo degenerative changes. Nodules may also develop when colloid accumulates in hyperplastic cells (colloid cysts). Uptake of radioiodine on scan is heterogeneous; some areas may not take up iodine and appear “cold.” The thyroid gland feels less firm than it does in Hashimoto disease. The TSH level may be slightly reduced, reflecting the autonomous nature of the thyroxine output of the gland, but free thyroxine levels are usually within normal limits.

Cancers

Cancers may arise in a multinodular gland, although this is very uncommon. Thyroid cancer and lymphoma are the leading causes. Cervical adenopathy, hoarseness (resulting from recurrent laryngeal nerve compression), and the continued enlargement of a “cold” nodule on thyroid scan are distinguishing features of the clinical presentation. A history of head and neck irradiation and family history of thyroid cancer (suggestive of hereditary disease) are risk factors. The nodule may be tender if the tumor is rapidly growing (as with lymphoma), a finding atypical of other multinodular goiters. Occasionally, metastases to the thyroid occur, primarily from breast and renal cell carcinoma.

Incidentalomas

The term “incidentaloma” is used to refer to a nonpalpable thyroid nodule detected incidentally in the course of imaging of the neck area by ultrasonography or other sensitive diagnostic modalities (e.g., computed tomography or magnetic resonance imaging). The risk for malignancy is low when the diameter of the lesion is less than 1.5 cm. Even if some incidentalomas represent early papillary cancers, the rate of growth is likely to be very slow for lesions smaller than 1.5 cm.

DIFFERENTIAL DIAGNOSIS (4,17)

The vast majority of solitary nodules are benign, even those that fail to take up radionuclide on thyroid scan (see later discussion). In the United States, Hashimoto thyroiditis accounts for the majority of cases of multinodular goiter. Cancers account for about 10% to 20% of solitary thyroid nodules; the prevalence is lower in patients with multinodular glands (Table 95-1).