Overview of thyroid nodule formation

INTRODUCTION — This topic will review the prevalence, risk factors, risk of cancer, and etiology of thyroid nodules. An understanding of these factors is essential in developing a reasonable diagnostic approach to patients with these thyroid nodules. (See "Diagnostic approach to and treatment of thyroid nodules".)

EPIDEMIOLOGY — Nodularity of thyroid tissue is extremely common. In a large population study (Framingham, MA), as an example, clinically apparent thyroid nodules were present in 6.4 percent of women and 1.5 percent of men [1]. These figures significantly underestimate the true frequency of this disorder, as evidenced by the following:

●In surveys of unselected subjects using ultrasonography, 20 to 76 percent of women had at least one thyroid nodule [2,3]. In Germany, an area of relative iodine deficiency, 96,278 screening ultrasounds found thyroid nodules or goiter in 33 percent of men and 32 percent of women; nodules over 1 cm were found in 11.9 percent of the population [4].

The prevalence of nodular goiter increased with age from 2.7 and 2.0 percent in women and men aged 26 to 30 years, to 8.7 and 6.7 percent in women and men aged 36 to 40 years, to 14.1 and 12.4 percent in women and men aged 45 to 50 years, and to 18.0 and 14.5 percent in women and men over age 55 years [4].

●In several autopsy surveys, 37 to 57 percent of patients had thyroid nodules [5,6].

●In patients with a single palpable nodule, from 20 to 48 percent had additional nodules as detected by ultrasonography [7].

Thus, while many nodules are detected because of their size or anterior position in the neck, or the skill of the clinician performing the examination, most thyroid nodules are not clinically recognized.

CAUSES AND RISK FACTORS — The major causes of benign and malignant thyroid nodules are listed in the table (table 1).

●Increased risk – Factors associated with an increased risk of thyroid nodules and goiter include:

•Smoking, especially in areas of mild iodine deficiency [8].

•Obesity and metabolic syndrome have been associated with thyroid nodules in observational studies [9,10], but assessment by Mendelian randomization does not suggest a causal relationship except in those with a high genetic susceptibility for type 2 diabetes [11]. Obesity is also associated with higher TSH values, thought to be mediated by higher leptin levels. Thus, both insulin resistance with hyperinsulinemia, and higher TSH values, may be contributing to the association of obesity with goiter [12].

•Alcohol consumption is associated with thyroid enlargement, more so in women [13].

•Insulin-like growth factor 1 (IGF-1) levels – Associated with nodules in men and goiter in both men and women [14].

•Uterine fibroids – In one report, women with fibroids had a twofold-increased risk of thyroid nodules compared with women with a normal uterus [15].

●Decreased risk – Factors associated with a possible decreased risk include:

•Oral contraceptive use [16].

•Use of statins (associated with a reduced risk of nodules on ultrasound) [17].

RATE OF CANCER — Unless thyroid nodules, single or multiple, cause obstruction or are cosmetically disturbing, their mass alone does not cause trouble. The main concerns then are: (1) whether or not they are cancers or, if they are, whether they are lethal, and (2) whether or not they cause thyroid dysfunction. (See "Diagnostic approach to and treatment of thyroid nodules" and "Treatment of toxic adenoma and toxic multinodular goiter".)

Most thyroid nodules are benign. Surgical series suggesting that 20 to 40 percent of thyroid nodules are cancers all had significant selection bias. Two reports probably provide a more accurate estimate of the true frequency of thyroid cancer among patients with thyroid nodules:

●In a community hospital in North Carolina where most patients with nodules were referred for surgery without benefit of biopsy, 6.5 percent of excised nodules were cancers [18].

●In Catania, Italy, 2327 patients presenting with nodules were evaluated by fine-needle aspiration (FNA) biopsy, and 391 were selected for surgery [19]. Cancers were found in 28 percent of the surgical specimens, which represented only 5 percent of all nodules.

However, in Boston, among patients referred to a thyroid practice, the rate of malignancy in thyroid nodules was 14 percent [20].

Differentiated thyroid cancers (papillary and follicular), which account for approximately 90 percent of all thyroid cancers, usually have a good prognosis [21]. This is particularly true in younger patients; as an example, the long-term (25-year) mortality of patients under age 40 years with papillary cancers was less than 2 percent after primary surgical therapy [22].

The frequency of occult papillary thyroid microcarcinomas (less than 1 cm in size) is much higher. In the United States, as an example, 6 to 13 percent of all thyroid glands studied at autopsy contain a papillary microcarcinoma [23,24]. The prevalence is substantially higher in some other countries, reaching 36 percent in Finland [25]. Thus, microcarcinomas are common and are little threat to life.

However, the natural history of microcarcinomas is uncertain. Approximately 15 percent of all differentiated thyroid cancers may behave in an aggressive manner [21]. They can metastasize and, in older patients who present with a cancer that invades through the thyroid capsule, the long-term mortality is 35 to 65 percent [22,26]. Anaplastic carcinomas, some medullary cancers, and thyroid lymphomas are also associated with higher mortality but are encountered less commonly than differentiated thyroid cancer [21].

Risk factors for cancer — Several risk factors for the development of thyroid cancer have been identified in non-iodine-deficient populations, including age, sex, and history of thyroid irradiation.

●Thyroid nodularity increases with age [6]. The presence of a thyroid nodule in a child is twice more likely to be a cancer than if it was in an adult [19].

●Among patients with thyroid nodules, the rate of cancer is twice as high in men than women (8 versus 4 percent), and it is higher in adults over age 60 and under age 30 years than in those aged 30 to 60 years [27].

●A history of radiation treatment to the head and neck region to treat acne, inflammation of the tonsils or adenoids, or thymic enlargement is associated with an increased incidence of thyroid nodularity and cancer [28]. In two large series, 20 to 27 percent of patients had thyroid nodularity and 30 to 33 percent of the nodules were cancers; however, some were microcarcinomas [29,30]. There is no evidence that radiation-associated thyroid cancers are more aggressive than other thyroid cancers [28,31].

●Hematopoietic stem cell transplantation increases the relative risk (RR) for thyroid cancer to 3.26; if transplantation occurred prior to age 10, the RR was 24.6 [32].

Size — Thyroid cancer appears to be more common in nodules ≥2 cm compared with <2 cm [33]. In one study of 4955 patients, the risk of malignancy in nodules 1.0 to 1.9 cm was 10.5 percent, while the risk in nodules 2.0 to 2.9, 3.0 to 3.9, or greater than 4 cm was 14, 16, and 15 percent, respectively [34]. While larger nodule size over 2 cm was not associated with an increased risk of malignancy, the proportion of papillary cancers reduced from 92 to 74 percent, while the proportion of follicular cancers increased from 6 to 16 percent as nodules increased from under 2 to over 4 cm.

ETIOLOGY OF NODULE FORMATION — The possible role of oncogenes and tumor suppressor genes in the pathogenesis of these lesions is discussed separately. (See "Oncogenes and tumor suppressor genes in thyroid nodules and nonmedullary thyroid cancer".)

Macrofollicular nodules — Benign macrofollicular thyroid nodules represent two distinct processes: true monoclonal adenomas [35] and colloid nodules in a multinodular goiter. Most of the latter nodules are also monoclonal [36,37]; they represent the expansion of relatively clonogenic cells, which replicate in nodular fashion. Both polyclonal and monoclonal nodules appear similar on fine-needle aspiration (FNA; macrofollicular) and are benign [38,39].

Follicular neoplasms (microfollicular adenomas) — Follicular neoplasms (microfollicular or cellular "adenomas") represent a unique diagnostic problem. They differ from follicular carcinomas only by their lack of capsular or vascular invasion [38,39]. Thus, the diagnosis of follicular cancer in situ does not exist, because vascular or capsular invasion is required to make the diagnosis of follicular cancer. Until recently, most microfollicular lesions were excised to exclude cancer, unless they were shown to have autonomous function demonstrated by thyroid scintigraphy. FNA biopsy of autonomous nodules may demonstrate a microfollicular pattern, but these nodules are virtually always benign [40]. (See "Diagnostic approach to and treatment of thyroid nodules", section on 'Thyroid scintigraphy'.)

Molecular markers, either an mRNA gene expression classifier or mutational analysis, have been used to triage follicular neoplasms for excision versus observation. The use of molecular markers in the evaluation of follicular neoplasms is reviewed in detail separately. (See "Evaluation and management of thyroid nodules with indeterminate cytology in adults", section on 'Molecular markers'.)

Multinodular goiters — The process of goitrogenesis is distinct from true neoplasia [36,38,39,41]. It was, therefore, assumed that multinodular goiters were unlikely to contain a cancer. Several studies have suggested that the frequency of cancer in nodular goiters is approximately 25 to 60 percent of that in solitary nodules [42-44].

However, a retrospective study of patients with multinodular goiter with one or more dominant nodules who underwent ultrasound-guided FNA biopsy found that 5 percent had thyroid cancers, which is the frequency in patients with solitary nodules [45]. In another study, the risk of malignancy was similar in a patient with a single or multiple nodules, but the risk of malignancy was higher in a solitary nodule than in a non-solitary nodule [20]. Thus, despite the tendency to preferentially biopsy the dominant nodule in a multinodular goiter, in one study, half of the cancers in a multinodular goiter were in non-dominant nodules [46].

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topics (see "Patient education: Thyroid nodules (The Basics)" and "Patient education: Nodular goiter (The Basics)")

●Beyond the Basics topics (see "Patient education: Thyroid nodules (Beyond the Basics)")

SUMMARY

●Epidemiology – Nodular thyroid tissue is extremely common. In one study, clinically apparent thyroid nodules were present in 6.4 percent of women and 1.5 percent of men. However, in surveys of unselected subjects using ultrasonography, 20 to 76 percent of women had at least one thyroid nodule. (See 'Epidemiology' above.)

●Major causes of benign thyroid nodules – The major causes of benign thyroid nodules are multinodular goiter, Hashimoto's thyroiditis, and follicular adenomas (table 1). (See 'Causes and risk factors' above.)

●Rate of cancer – Most thyroid nodules are benign. Thyroid cancer occurs in 5 to 15 percent of thyroid nodules. The incidence depends in part upon age, sex, radiation exposure, and family history. (See 'Rate of cancer' above.)