The Evaluation and Management of Thyroid Nodules

Clinical Risk Factors

Thyroid nodule evaluation begins with history and physical examination focused on the thyroid and cervical neck. In general, risk factors for nodules include increased age, female sex, obesity, and iodine deficiency. Nodules may be identified at differing rates depending on survey method (e.g., ultrasound versus palpation). Therefore thresholds to perform these elements or extensions of physical examination should be considered based on symptomatology or risk of malignancy. Malignancy occurs in approximately 8% to 15% of cases, and risk is similarly influenced by clinical variables, such as sex, age, and the presence of unique symptoms or examination findings. Elements of patient history that are concerning for thyroid malignancy include history of childhood irradiation to the head and neck, exposure to radioactive fallout, family history of thyroid cancer in a first-degree relative, or family history of hereditary syndromes associated with thyroid cancer (e.g., multiple endocrine neoplasia type 2 [MEN 2] association with hereditary medullary thyroid cancer [MTC]).

Family History and Radiation Exposure

The strongest risk factors for differentiated thyroid cancer (DTC) are family history and prior head and neck radiation exposure. Family history of DTC is a known risk factor for thyroid malignancy. Epidemiologic evidence shows that 5% to 10% of DTCs have a familial occurrence; however, it is often unclear whether diagnosis of DTC in patients with a positive family history represents familial versus sporadic disease. Pedigrees showing one to two family members with thyroid cancer are not uncommon; evidence shows that the chance of nonmedullary DTC being sporadic is much lower when three or more family members are affected (< 6% sporadic), compared with two or fewer (62% to 69%). Syndromes associated with DTC in a first-degree relative include phosphatase and tensin homolog (PTEN) hamartoma tumor syndrome (i.e., Cowden’s disease), familial adenomatous polyposis (FAP), and Carney complex.

Thyroid exposure to ionizing radiation during childhood imparts significant risk for malignancy, because the thyroid is among the most radiosensitive organs. Importantly, radiation exposure increases thyroid cancer risk predominantly when the exposure occurs during childhood. Risk is most significant when exposure occurs at < 5 years of age, and no increased risk is observed when exposure occurs beyond 20 years of age. Further, radiation-induced cancers often harbor mutations that convey more aggressive clinical behavior, including a high prevalence of RET/PTC (reaaranged during transfection/papillary thyroid carcinoma) chromosomal rearrangement. Annual thyroid examination by palpation (though not routine ultrasound) has been advocated for survivors of childhood cancer previously treated with neck radiation.

The Chernobyl nuclear power station explosion in 1986 is a notable example of widespread radiation exposure, and the effects of this exposure on thyroid cancer risk have been well studied. It is estimated that this exposure was responsible for > 4000 new cases of thyroid cancer between 1986 and 2002 in Belarus, Russia, and Ukraine. A nearly 150-fold increase in incidence between 1986 and 1996 has been recorded in the most heavily-contaminated regions of Belarus (0.085 to 12.6 per 100,000 children/year). A similar trend was seen after the Fukushima Daiichi nuclear power plant accident in 2011.

Age and Sex

Increasing prevalence of nodular disease is observed as patient age increases. In a large prospective cohort analysis of more than 6000 patients with more than 12,000 thyroid nodules, Kwong et al. found that the average number of thyroid nodules increased with age (1.6% annual increased risk for multinodularity); however, there was a lower risk of malignancy in newly-identified nodules with advancing age (2.2% annual decrease in relative risk of malignancy between 20 to 60 years of age). Despite the latter finding, older patients were also observed to have higher-risk histologic phenotypes. Although older patients are at increased risk for high-risk cancer, the number of individuals with high-risk cancer is low; older patients with nodular thyroid disease and additional comorbidities, such as other cancers and coronary artery disease, are more likely to die of their comorbidities.

The incidence of thyroid cancer is highest in patients age 65 and older. The balance of treatment risks and benefits is shifted in favor of more conservative care in the older patient population. Advanced age is more associated with higher rates of thyroid-specific surgical complications than historically reported in literature, with hypocalcemia and vocal fold paralysis observed in up to 13.6% and 7.1% to 9.5% of patients > 65 years, respectively. The increased risk of thyroid cancer recurrence and disease-specific mortality in older patients argues in favor of surgical management, and it is reflected in more advanced staging schema for patients ≥ 55 years in the updated American Joint Committee on Cancer (AJCC) 8th edition staging system. However, limited life expectancy, significant comorbidities, and risk of surgical complications argue in favor of more conservative treatment or observation. Therefore advanced age is an important factor when considering surgical intervention for thyroid nodules.

Thyroid cancer is three times more common in women, but men evaluated for thyroid nodules are more likely to have a thyroid malignancy. In a retrospective study of nearly 2000 nodule patients with more than 3500 thyroid nodules, the rate of thyroid cancer in men was nearly double that of women. The biological mechanism for this increased risk is unclear; however, this trend is, in part, explained by the much higher incidence of thyroid nodules identified in women overall.