Diagnostic approach to and treatment of thyroid nodules

INTRODUCTION — Thyroid nodules come to clinical attention when noted by the patient; by a clinician during routine physical examination; or during a radiologic procedure, such as carotid ultrasonography, neck or chest computed tomography (CT), or positron emission tomography (PET) scanning. Their clinical importance is primarily related to the need to exclude thyroid cancer, which accounts for 4 to 6.5 percent of all thyroid nodules in nonsurgical series.

The diagnostic evaluation and treatment of thyroid nodules will be reviewed here. Fine-needle aspiration (FNA) techniques, common cytopathologic findings, and evaluation and management issues specific to indeterminate cytologies, are reviewed elsewhere.

●(See "Thyroid biopsy".)

●(See "Atlas of thyroid cytopathology".)

●(See "Evaluation and management of thyroid nodules with indeterminate cytology in adults".)

●(Related Pathway(s): Thyroid nodules: Initial evaluation in adults.)

●(Related Pathway(s): Thyroid nodules: Initial evaluation in pregnant patients.)

EVALUATION — Several different disorders can cause thyroid nodules (table 1). The clinical importance of the thyroid nodule evaluation is primarily related to the need to exclude thyroid cancer, which is present in 4 to 6.5 percent of thyroid nodules [1-5]. The prevalence of cancer is higher in several groups:

●Children

●Adults less than 30 years of age

●Patients with a history of head and neck irradiation

●Patients with a family history of thyroid cancer

In one study from Sicily [2], but not in another study from Boston [5], the prevalence of cancer was higher in adults over 60 years.

Our approach (algorithm 1) described below is consistent with the American Thyroid Association (ATA) and the National Comprehensive Cancer Network (NCCN) guidelines [6,7]. (Related Pathway(s): Thyroid nodules: Initial evaluation in pregnant patients and Thyroid nodules: Initial evaluation in adults.)

Initial — Thyroid nodules come to clinical attention when noted by the patient; during routine physical examination; or when incidentally noted during a radiologic procedure, such as carotid ultrasonography, neck or chest computed tomography (CT), magnetic resonance imaging (MRI), or positron emission tomography (PET) scanning. Nonpalpable nodules (incidentalomas) have the same risk of malignancy as palpable nodules of the same size [8-11]. Thus, the initial evaluation in all patients with a thyroid nodule (discovered either by palpation or incidentally noted on a radiologic procedure) includes:

●History and physical examination

●Measurement of serum thyroid-stimulating hormone (TSH)

●Ultrasound to confirm the presence of nodularity, assess sonographic features, and assess for the presence of additional nodules and lymphadenopathy

History and physical examination — The history and physical examination have a low accuracy for predicting cancer. However, there are several features of the history that suggest an increased likelihood of malignancy, such as a history of rapid growth of a neck mass, childhood head and neck irradiation, total body irradiation for bone marrow transplantation, family history of thyroid cancer, or thyroid cancer syndromes (eg, multiple endocrine neoplasia type 2 [MEN2], familial adenomatous polyposis, or Cowden syndrome). (See "PTEN hamartoma tumor syndromes, including Cowden syndrome" and "Clinical manifestations and diagnosis of familial adenomatous polyposis" and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2".)

The physical examination findings of a fixed hard mass, obstructive symptoms, cervical lymphadenopathy, or vocal cord paralysis all suggest the possibility of cancer.

Serum TSH — Thyroid function should be assessed in all patients with thyroid nodules (algorithm 1). (See 'TSH low' below and 'TSH normal or high' below.)

Serum TSH is an independent risk factor for predicting malignancy in a thyroid nodule. In a study of 1500 patients presenting to a thyroid practice, the prevalence of malignancy was 2.8, 3.7, 8.3, 12.3, and 29.7 percent for patients with serum TSH concentrations <0.4 mU/L, 0.4 to 0.9 mU/L, 1 to 1.7 mU/L, 1.8 to 5.5 mU/L, and >5.5 mU/L, respectively [12]. Other studies have shown that when cancer was diagnosed, a higher TSH was associated with a more advanced stage of cancer [13,14].

Thyroid ultrasonography — Thyroid ultrasound should be performed in all patients with a suspected thyroid nodule or nodular goiter on physical examination or with nodules incidentally noted on other imaging studies (carotid ultrasound, CT, MRI, or fludeoxyglucose [FDG]-PET scan). The routine use of thyroid ultrasound as a screening tool to detect nonpalpable thyroid cancers in patients without known or suspected thyroid nodules is not recommended [7,15].

●Provides more information than physical examination – Thyroid ultrasonography is used to answer questions about the size and anatomy of the thyroid gland and adjacent structures in the neck. It provides considerably more anatomic detail than thyroid scintigraphy [16], CT [17], and physical examination [18,19]. (See "Overview of the clinical utility of ultrasonography in thyroid disease", section on 'Nodule identification and characterization'.)

In a retrospective study of 173 patients referred to a thyroid nodule clinic for an abnormal thyroid examination, the ultrasound findings were different from the physical examination done by the referring clinician in 63 percent of cases [19]. Of the 114 patients referred for a solitary nodule, 24 percent had additional nodules and 20 percent did not have a nodule of at least 1 cm that required aspiration. (See 'Sonographic criteria for FNA' below.)

Ultrasound can identify posteriorly located nodules or predominantly cystic nodules. The diagnostic accuracy of FNA performed by palpation is reduced in these nodules, and ultrasound-guided FNA is more effective (see "Thyroid biopsy", section on 'Ultrasound guidance'). Apparent nodularity in Hashimoto's thyroiditis may represent focal enlargement from lymphocytic infiltrates, TSH-induced hyperplasia of follicular tissue, or a thyroid tumor. Ultrasonography may also help to distinguish among these possibilities.

●Helps select nodules for FNA – There are several ultrasonographic findings that are suspicious for thyroid cancer (table 2 and table 3 and table 4). The predictive value of these characteristics varies widely, and we do not rely on thyroid ultrasound to diagnose cancer or to select patients for surgery. However, ultrasound findings can be used to select nodules for FNA biopsy. (See 'Sonographic criteria for FNA' below and "Overview of the clinical utility of ultrasonography in thyroid disease", section on 'Criteria for identifying cancer'.)

Subsequent evaluation — Subsequent evaluation is based upon the TSH level and sonographic features of the nodule(s) (algorithm 1).

TSH low — If the serum TSH concentration is subnormal, indicating overt or subclinical hyperthyroidism, the possibility that the nodule is hyperfunctioning is increased and thyroid scintigraphy should be performed next (algorithm 1). Thyroid hormone production from some autonomous nodules may suppress TSH only within the lower portion of the normal range (eg, <1 mU/L). Scintigraphy may be informative in such patients, especially if prior TSH levels were subnormal, or when the results of an FNA suggest a follicular neoplasm. (See 'Thyroid scintigraphy' below and "Evaluation and management of thyroid nodules with indeterminate cytology in adults".)

Patients with TSH below the normal range also require an evaluation for hyperthyroidism. (See "Diagnosis of hyperthyroidism", section on 'Diagnosis'.)

Thyroid scintigraphy — Thyroid scintigraphy is used to determine the functional status of a nodule. A subnormal serum TSH, indicating overt or subclinical hyperthyroidism, increases the possibility that a thyroid nodule is hyperfunctioning. Since hyperfunctioning nodules rarely are cancer, a nodule that is hyperfunctioning on radioiodine imaging does not require FNA. In addition, thyroid scintigraphy may be useful in patients with multiple thyroid nodules to select those that are hypofunctional and therefore may require FNA. Although thyroid scintigraphy can be used to select nodules for FNA, it cannot be used to select patients for surgical resection.

Radionuclide scanning is contraindicated during pregnancy. If a woman is breastfeeding, breastfeeding should be suspended if a radionuclide scan is obtained. The amount of time will depend on which isotope is used (breastfeeding needs to be suspended longer if radioiodine is used). (See "Overview of thyroid disease and pregnancy", section on 'Thyroid nodules'.)

Scintigraphy utilizes one of the radioisotopes of iodine (usually 123-I) or technetium-99m pertechnetate. If available, radioiodine scanning is preferred. These radioisotopes are handled differently by thyroid follicular cells. Normal thyroid follicular cells take up both technetium and radioiodine, but only radioiodine is organified and stored (as thyroglobulin) in the lumen of thyroid follicles [20]. Most benign and virtually all malignant thyroid nodules concentrate both radioisotopes less avidly than adjacent normal thyroid tissue (image 1). However, 5 percent of thyroid cancers concentrate pertechnetate but not radioiodine [20]. These nodules may appear hot or indeterminate ("warm") on pertechnetate scans and cold on radioiodine scans. Although most are benign nodules [21-23], a few are thyroid cancers [22,24,25]. As a result, patients with nodules that are functioning on pertechnetate imaging should undergo radioiodine imaging to confirm that they are actually functioning [22,26]. However, if the pertechnetate scan shows unequivocal increased uptake in a nodule with suppression of uptake elsewhere in the thyroid and an undetectable TSH, a radioiodine scan may not be necessary.

●Nonfunctioning – Nonfunctioning nodules appear cold (uptake less than surrounding thyroid tissue) (image 1), and they may require further evaluation by FNA. (See 'Sonographic criteria for FNA' below.)

●Autonomous – Autonomous nodules may appear hot (uptake is greater than surrounding thyroid tissue) (image 2) if they are hyperfunctioning. Autonomous nodules that do not make sufficient thyroid hormone to suppress serum TSH concentrations will appear indeterminate on thyroid scintigraphy. Autonomous nodules account for only 5 to 10 percent of palpable nodules. Only a few patients with autonomous nodules have been found to have thyroid cancer [27-29], and only a few of these cancers were aggressive [30]. Furthermore, in some of these patients, the cancer was adjacent to the autonomous nodule rather than within it. Since hyperfunctioning nodules rarely are cancer, a nodule that is hyperfunctioning on radioiodine imaging does not require FNA. (See 'Autonomous nodules' below.)

●Indeterminate – Because scintigraphy is two dimensional, its limitations result from the superimposition of abnormal nodular tissue and normally functioning thyroid tissue (image 3). Thus, while over 80 percent of nonautonomous nodules greater than 2 cm appear cold, smaller nodules present as a filling defect in less than one-third of cases [27]. The remaining majority of smaller nodules are indeterminate on thyroid scintigraphy [31]. They could represent either small, nonfunctioning nodules anterior or posterior to normally functioning thyroid tissue, or autonomous nodules that do not produce sufficient thyroid hormone to suppress TSH (image 4).

These indeterminate nodules should not be referred to as warm or functioning, since the majority are, in fact, nonfunctioning nodules. Indeterminate nodules on scintigraphy should be evaluated by FNA if they meet sonographic criteria for sampling. (See 'Sonographic criteria for FNA' below.)

TSH normal or high — If the serum TSH concentration is normal or elevated and the nodule meets sonographic criteria for sampling (table 3 and table 4), the next step in the evaluation of a thyroid nodule is an ultrasound-guided FNA biopsy; a palpation FNA biopsy may be performed if ultrasound is not available (algorithm 1). FNA biopsy is the most accurate method for evaluating thyroid nodules and identifying patients who require surgical resection [7,32]. FNA biopsy has resulted in improved diagnostic accuracy, a higher malignancy yield at the time of surgery, and significant cost reductions [32-34].

Nodules that do not meet sonographic criteria for FNA should be monitored. (See 'Monitoring of nodules that do not meet FNA criteria' below.)

Patients with a high serum TSH concentration require an evaluation for hypothyroidism. (See "Diagnosis of and screening for hypothyroidism in nonpregnant adults" and "Disorders that cause hypothyroidism".)

Fine-needle aspiration biopsy

Sonographic criteria for FNA — Thyroid nodules are selected for FNA based on suspicious ultrasonographic characteristics rather than size alone, as the presence of suspicious ultrasound features is more predictive of malignancy [10,35].

●Decision analyses for selecting nodules for FNA – There are several approaches used to categorize thyroid nodules for likelihood of malignancy and to select nodules for biopsy. The American College of Radiology has proposed a system (Thyroid Imaging, Reporting and Data System [TIRADS]) for selecting nodules for FNA (table 3) [36]. Similar, but not identical systems have been proposed in Europe, South Korea, and China (also called TIRADS) [37-40]. The ACR-TIRADS is more selective than the approach taken by the 2015 ATA guidelines (table 4) [7,41]. It is also considerably more complex than the ATA criteria [42]. With TIRADS, suspicious sonographic features are assigned points, and the nodules are categorized as TR1 to 5 based on total points with increasing likelihood of malignancy. Category 3, 4, or 5 nodules are considered candidates for biopsy if the nodules are 25, 15, or 10 mm in size, respectively (calculator 1). These size cutoffs for FNA of thyroid nodules are higher for TR3 and TR4 nodules than those recommended by the ATA (table 4) [36,37]. (See "Overview of the clinical utility of ultrasonography in thyroid disease", section on 'Criteria for identifying cancer'.)

The various decision analyses differ in diagnostic performance and yield of FNA [43-46]. ACR-TIRADS reduces the number of biopsies done and improves accuracy [44]. In a meta-analysis of 12 studies and 18,750 nodules, it was superior to the approach taken by the 2015 ATA guidelines [45].

●Our approach – Our approach is largely consistent with ACR-TIRADS (table 3), but in anxious patients who are strongly motivated towards a biopsy, we may apply the less selective ATA guidelines (table 4).

•Since active surveillance is considered safe for many papillary microcarcinomas, we generally do not biopsy highly suspicious (TR5) nodules under 10 mm (table 3). However, since active surveillance is not recommended for papillary microcarcinoma with certain high-risk features, we consider FNA (if achievable) in any TR5 nodule (regardless of size) with these suspicious sonographic features:

-Subcapsular locations adjacent to the recurrent laryngeal nerve (RLN) or trachea (the right RLN is located posterior and lateral to the right lobe, while the left RLN is posterior and medial)

-Extrathyroidal extension

-Extrusion through rim calcifications

-Associated with sonographically abnormal cervical lymph nodes

Thyroid nodules under 5 mm are technically difficult to biopsy; before considering such a biopsy, the risk of a nondiagnostic result and the reliability of a negative result should be discussed with the patient. In the presence of abnormal cervical lymph nodes, FNA cytology may be obtained from the abnormal lymph node if the nodule is not amenable to FNA. (See "Thyroid biopsy", section on 'Lymphadenopathy'.)

•FNA should be performed in nodules that are solid and hypoechoic if they are ≥1.5 cm (as determined by largest dimension). FNA should be performed in nodules that are solid and hypoechoic if they are ≥1 to 1.5 cm with one of these suspicious sonographic features:

-Irregular margins (≥1.5 cm)

-Microcalcifications (≥1 cm)

-Taller-than-wide shape (≥1 cm)

-Macrocalcifications (≥1.5 cm)

-Peripheral (rim) calcifications (≥1.5 cm)

-Any combination (≥1 cm)

The estimated risk of malignancy for hypoechoic solid nodules with one or more suspicious sonographic features is higher (35 to 90 percent) than for hypoechoic solid nodules without additional suspicious features (9 to 20 percent) (table 3 and table 4). While the ATA also suggests ≥1 cm as their threshold for FNA in hypoechoic solid nodules without suspicious characteristics (table 4), the American College of Radiology-Thyroid Imaging Reporting and Data System (ACR-TIRADS) use a threshold of ≥15 mm (table 3). This decreases the number of benign and therefore unnecessary biopsies.

•FNA can be considered in selected patients with nodules <1 cm if there is a strong family history of differentiated thyroid cancer (defined as at least two first-degree relatives), known syndromes associated with thyroid cancer, young age, a history of therapeutic childhood head and neck or whole-body radiation, or preference for FNA over observation. However, most patients with suspicious subcentimeter nodules can be observed [47]. Ideal candidates for observation of suspicious subcentimetric nodules include older patients (age >60 years), especially those with comorbidities, with solitary nodules with well-defined margins and a >2 mm rim of normal thyroid parenchyma; however, observation is also considered acceptable in all adult patients and those with multiple nodules. (See 'Monitoring of nodules that do not meet FNA criteria' below.)

•Nodules with sonographic appearance suggesting a low risk for thyroid cancer (isoechoic, hyperechoic, or partially cystic without suspicious characteristics in the solid component, estimated risk of malignancy 5 to 10 percent) can be biopsied when ≥2.5 cm (table 3). These criteria apply to both palpable and nonpalpable nodules. This recommendation is based upon observational studies that show similar rates of cancer in nonpalpable nodules >1 cm and palpable nodules of similar size [9,11].

•Spongiform nodules, defined as an aggregation of multiple microcystic components in more than 50 percent of the nodule volume, do not require FNA regardless of size (estimated risk of malignancy under 3 percent).

•Purely cystic nodules (no mural component) do not require a biopsy.

FNA technique — Tissue for histologic or cytologic examination may be obtained from the thyroid by several different techniques, including cutting needle biopsy, large- or fine-needle aspiration, or fine-needle capillary sampling. FNA biopsy is the most commonly used approach. A complete discussion of the techniques, their value and limitations, and potential complications can be found elsewhere. (See "Thyroid biopsy".)

FNA is a simple and safe office procedure in which tissue samples are obtained for cytologic examination using 23- to 27- gauge (commonly 25-gauge) needles with or without local anesthesia. With experience, adequate samples can be obtained in 90 to 97 percent of aspirations of solid nodules.

Ultrasound-guided FNA biopsy should be performed for nonpalpable nodules and for nodules that are technically difficult to aspirate using palpation methods alone, such as predominantly cystic or posteriorly located nodules. In patients with large nodules (>4 cm), ultrasound-guided FNA directed at several areas within the nodule may reduce the risk of a false-negative biopsy. (See "Thyroid biopsy", section on 'Ultrasound guidance' and "Cystic thyroid nodules".)

Multiple nodules — Patients with multiple nodules have the same risk of malignancy as those with a single nodule, although the risk of cancer in each individual nodule in a patient with multiple nodules is lower than the risk of cancer in a nodule in a patient with only one nodule [19,35]. Thus, the sonographic features of each nodule should be assessed independently to determine the need for FNA biopsy. If there are multiple coalescent nodules and none have suspicious sonographic features, FNA biopsy of the largest nodule is reasonable [7]. The nodules that are not biopsied should be monitored with periodic ultrasonography. (See 'Monitoring of nodules that do not meet FNA criteria' below.)

Monitoring of nodules that do not meet FNA criteria — Nodules that do not meet sonographic criteria for FNA should be monitored. The frequency of evaluation depends upon the sonographic features of the nodules [47]. We perform periodic ultrasonography initially at:

●6 to 12 months for subcentimeter nodules with suspicious characteristics

●12 to 24 months for nodules with low to intermediate suspicion on ultrasound

●2 to 3 years for very-low-risk nodules

Subsequent ultrasounds can be obtained at increasing intervals over time, depending upon stability. Nodules that enlarge significantly should be assessed for FNA, and subcentimeter nodules that grow to ≥1 to 2.5 cm require a biopsy depending upon their size and ultrasound characteristics (table 3 and table 4).

Evidence for an observational approach to subcentimeter nodules without suspicious ultrasound features comes from a prospective Italian study of the natural history of thyroid nodules, in which 992 patients (without apparent risk factors for thyroid cancer, but mild to moderately iodine deficient) with 1567 nodules were monitored with yearly thyroid ultrasound for five years [48]. During follow-up, only one cancer was diagnosed among the 852 subcentimeter thyroid nodules lacking high-risk ultrasound features. This nodule was biopsied due to the development of suspicious ultrasound features (hypoechogenicity, irregular margins), not growth. FNA biopsy was not performed on all of the nonsuspicious nodules, and therefore, this study cannot rule out the presence of asymptomatic, latent thyroid cancer. Additionally, the etiology and natural history of nodules in iodine-deficient regions may differ from that in iodine-sufficient regions such as the United States. Overall, however, the absence of suspicious ultrasound features on baseline examination is a reassuring finding in patients with subcentimeter nodules.

Serum calcitonin concentration — The routine measurement of serum calcitonin in patients with nodular thyroid disease is controversial [49-51]. At present, we agree with others that the routine use of basal calcitonin measurements in nodular thyroid disease is not warranted in countries (eg, United States, Canada) where the use of pentagastrin stimulation as a confirmatory test is not available [52,53]. If pentagastrin stimulation testing were available, some thyroid experts would routinely measure serum calcitonin in patients with nodular thyroid disease, whereas others would not [49-51,54]. The ATA notes the uncertainties surrounding calcitonin measurements and has not taken a position for or against calcitonin screening [7,55].

If the basal serum calcitonin level is measured and exceeds 10 pg/mL, the calcitonin measurement should be repeated after pentagastrin stimulation testing (after renal insufficiency and use of proton pump inhibitor medication have been ruled out) [56]. Calcium is also a calcitonin secretagogue; owing to the unavailability of pentagastrin in many countries, there is a growing interest in using the calcium stimulation test as a confirmatory test in patients with elevated basal calcitonin levels. However, few standardized data using modern calcitonin assays are available [57,58]. Pentagastrin and calcium stimulation testing are reviewed separately. (See "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Biochemical testing'.)

Several reports have suggested that serum calcitonin should be measured routinely in patients with nodular thyroid disease in order to identify those who have medullary thyroid cancer (MTC) at an earlier stage and to improve survival [59-70] . However, controversy remains about the routine use of serum calcitonin measurements because of the absence of uniform calcitonin thresholds to distinguish sporadic occult MTC [64,71-73], the high false-positive rate (59 percent or higher) in some studies, and the uncertain importance of small tumors [32,74]. (See "Medullary thyroid cancer: Clinical manifestations, diagnosis, and staging" and "Clinical manifestations and diagnosis of multiple endocrine neoplasia type 2", section on 'Medullary thyroid cancer'.)

Data on the utility of routine serum calcitonin measurement in patients with nodular thyroid disease are largely from prospective cohort studies . In various reports, basal serum calcitonin was increased in 0.5 to 5 percent of patients with thyroid nodules [63,66,69]. In a study of 1167 French patients with nodular thyroid disease, the prevalence of MTC in patients with elevated versus normal basal calcitonin levels was 41.1 and 0.17 percent, respectively [60].

In the studies that showed a diagnostic advantage to measuring basal serum calcitonin [56,60,63,70], however, serum calcitonin was repeated after pentagastrin (available only in some countries) stimulation to confirm MTC or C cell hyperplasia in those with elevated calcitonin levels. As an example, in one report of 10,864 patients screened after 1991, 44 (0.4 percent) had an elevated calcitonin, all confirmed by an elevated pentagastrin-stimulated calcitonin, and all had MTC [63]. Fifty-nine percent of these patients were in complete remission compared with only 2.7 percent of patients diagnosed with MTC prior to the use of routine screening, suggesting a benefit to early diagnosis. In contrast, in a study of 10,158 patients with thyroid nodules, 5 percent had elevated basal calcitonin, but only 20 percent of these patients had elevated values after pentagastrin stimulation and only 31 percent of these patients had MTC [66]. In all of these studies, calcitonin was more accurate than FNA for identifying MTC since many of the cancers were quite small. In the French study, only 2 of 12 patients diagnosed by calcitonin measurement had lesions that were 1 cm in diameter or larger, while four were less than 0.3 cm in diameter [60].

False-positive calcitonin results may be obtained in patients with hypercalcemia, hypergastrinemia, neuroendocrine tumors, renal insufficiency, papillary and follicular thyroid carcinomas, goiter, and chronic autoimmune thyroiditis [32,75]. Furthermore, prolonged treatment with omeprazole (greater than two to four months), beta blockers, and glucocorticoids have been associated with hypercalcitoninemia [76]. In addition, there are reports of rare MTCs that do not secrete calcitonin, and a false-negative test result may be expected [77,78].

Other laboratory tests — Routine measurement of serum antithyroid peroxidase (TPO) antibodies and thyroglobulin is not necessary.

Measurement of TPO antibodies may be helpful in patients with a high TSH suggestive of chronic autoimmune (Hashimoto's) thyroiditis. However, the presence of a high titer of TPO antibodies does not negate the need for FNA biopsy of a thyroid nodule in a patient with Hashimoto's thyroiditis. In a prospective study of 14,063 FNAs, the risk of malignancy was 23 percent in patients with coexisting Hashimoto's thyroiditis and 16 percent in those without thyroiditis [79]. Rapid shrinkage of the nodule when T4 (levothyroxine) therapy is instituted may be sufficiently reassuring to mitigate further concern. However, thyroiditis and thyroid cancer may coexist, particularly after head and neck irradiation [67,80]. Thus, a definite nodule, even in the presence of a high serum antibody concentration, requires further evaluation.

Serum thyroglobulin levels can be elevated in many thyroid diseases including benign goiter, hyperthyroidism, and any cause of a destructive thyroiditis. An elevated level does not help discriminate benign from malignant thyroid nodules. Thus, we do not measure serum thyroglobulin levels as part of the evaluation of patients with a thyroid nodule.

Thyroid incidentalomas — Incidentalomas are nonpalpable thyroid nodules that are detected during other imaging procedures. Nonpalpable nodules have approximately the same risk of malignancy as palpable nodules [8-11]. In some settings, especially nodules discovered on PET scan (see 'PET scans' below), the risk of malignancy may be higher, but in other settings (cystic nodules), it is lower.

Patients with a history of childhood head or neck irradiation — Radiation exposure of the thyroid during childhood is the most clearly defined environmental factor associated with benign and malignant thyroid tumors. There is a linear dose-response curve, with no evidence of a threshold at low doses. The risk reaches a plateau and possibly tapers off at high doses. (See "Radiation-induced thyroid disease".)

Many patients with a history of radiation exposure during childhood have nonpalpable thyroid nodules. This was illustrated by a report in which 54 such patients underwent thyroid ultrasonography [81]. Although most of the patients had no palpable nodules, 47 had 157 nodules on ultrasonography. The nodules ranged in size from a few millimeters to 3 cm. Eleven nodules were 1.5 cm or larger, six of which could be palpated.

The arguments for and against the routine use of ultrasonographic screening in patients with a history of radiation are reviewed in detail elsewhere. We recommend ultrasonography based upon an assessment of each patient's risk factors for thyroid cancer. (See "Radiation-induced thyroid disease", section on 'Surveillance for structural thyroid abnormalities'.)

PET scans — Thyroid nodules ≥1 cm with focal FDG uptake that are discovered incidentally on PET scans require ultrasound-guided FNA biopsy (image 5) [7]. However, if there is focal FDG uptake and the TSH is low, a radioiodine scan should be obtained to determine if the nodule is functional (autonomous) (see 'Thyroid scintigraphy' above). If the nodule is autonomous, it is unlikely to be malignant; however, there is insufficient evidence to be certain. While it is likely that FNA is not needed for these patients, the optimal approach is unclear, and obtaining an FNA is a reasonable approach in light of this uncertainty.

Many incidentalomas found on PET scans are thyroid cancers (differentiated thyroid cancer or MTC) [82-84]. In a systematic review of 22 studies evaluating incidentally found hypermetabolic activity in the thyroid gland by PET scan (1994 patients with unexpected focal hypermetabolic activity, 999 with unexpected diffuse activity), a diagnosis was assigned in 1051 and 168 patients, respectively [85]. Among those with a focal FDG uptake, 366 of 1051 (34.8 percent) had a thyroid malignancy compared with 7 of 168 patients (4.4 percent) with diffuse uptake. The mean maximum standardized uptake value (SUVmax) was 6.9 and 4.8 in malignant and benign lesions, respectively.

In a small, retrospective study of follicular neoplasms that had PET scans within a year of FNA and had surgical excision of the nodule, 1 of 19 (5 percent) FDG negative (<5 SUV) and 4 of 26 (15 percent) FDG positive (>5 SUV) were malignant [86].

Of note, Hashimoto's thyroiditis is often FDG avid with diffuse activity. As a result, if the patient has Hashimoto's thyroiditis, the PET images should be carefully reviewed to determine if the FDG uptake is truly focal and consistent with a nodule, rather than representing uptake by the entire gland.

Graves' disease — The prevalence of thyroid nodules and cancer in patients with Graves' disease has been investigated in a prospective study in which 245 patients with Graves' underwent screening ultrasonography. Thirty-five percent had nodules, and 3.3 percent had thyroid cancers (one of eight cancers was palpable) [87]. The risk of malignancy was higher in patients over age 45 years. We limit ultrasonography to Graves' patients with palpable abnormalities or heterogeneous or focal decreased uptake on thyroid scintigraphy. Ultimately, the decision to FNA is dependent upon ultrasound characteristics, rather than findings on thyroid scintigraphy, as it may be difficult to determine if a nodule is functional on scintigraphy since the nodule is surrounded by hyperactive thyroid tissue.

Cystic nodules — The majority of cystic thyroid nodules are benign, degenerating thyroid adenomas. However, thyroid cancers may be cystic. The presence of suspicious ultrasound features in mural tissue in the cystic nodule is more predictive of malignancy than nodule size alone. The decision to biopsy a thyroid nodule should be based upon a combination of ultrasonographic features of the solid component and nodule size (table 3 and table 4). The evaluation and management of cystic nodules are reviewed in more detail elsewhere. (See "Cystic thyroid nodules".)

Pregnancy — Thyroid radionuclide scanning is contraindicated during pregnancy. Otherwise, a pregnant woman found to have a thyroid nodule can be evaluated in the same way as if she were not pregnant. (See "Overview of thyroid disease and pregnancy", section on 'Thyroid nodules'.)

MANAGEMENT — The optimal therapy for patients with thyroid nodules varies with the lesion that is found and whether or not it is functioning.

FNA cytology — There are six major categories of results that are obtained from fine-needle aspiration (FNA), each of which indicates different subsequent management. The diagnostic categories (Bethesda classification) (table 5) and cytopathologic diagnoses of FNA results are reviewed in detail separately. (See "Thyroid biopsy", section on 'Diagnostic categories' and "Atlas of thyroid cytopathology".)

Benign nodules (Bethesda II)

Surveillance — Patients with benign nodules (macrofollicular or adenomatoid/hyperplastic nodules, colloid adenomas, nodular goiter, and Hashimoto's thyroiditis) are usually monitored without treatment. In the absence of a history of childhood neck irradiation, patients with benign nodules should not be treated with T4. (See "Thyroid hormone suppressive therapy for thyroid nodules and benign goiter".)

We perform periodic ultrasound monitoring of benign thyroid nodules, initially at 12 to 24 months, then at increasing intervals over time (eg, three to five years), with the shorter intervals for large nodules or nodules with worrisome ultrasound features and the longer interval for smaller nodules with classic benign ultrasonographic features. We repeat the FNA within 12 months if the nodule has highly suspicious ultrasound features despite a benign biopsy.

Small changes in nodule size on serial ultrasonography do not require a repeat aspiration. However, reassessment is warranted when there is any of the following [7,48]:

●Substantial growth (more than a 50 percent change in volume or 20 percent increase in nodule diameter with a minimum increase in two or more dimensions of at least 2 mm)

●Appearance of suspicious ultrasound features

●New symptoms are attributed to a nodule

If a nodule is re-aspirated and the second cytology is benign, ultrasound assessment of this particular nodule for possible risk of malignancy is no longer necessary [7,88]. If the second cytology is abnormal, treatment is based on the specific findings. (See "Evaluation and management of thyroid nodules with indeterminate cytology in adults" and 'Suspicious for malignancy (Bethesda V)' below and 'Malignant (Bethesda VI)' below.)

●Rationale for monitoring – The purpose of monitoring is to identify nodular growth, potentially indicating a falsely benign nodule. However, the false-negative rate of a benign interpretation is low (0 to 10 percent) [48,89-91]. Re-aspiration of thyroid nodules that are unchanged clinically is not warranted, because detection of malignancy is uncommon in routine repeat biopsies [92-96]. This was illustrated in two studies of 250 patients who had routine repeat FNA; only one previously benign nodule was found to be malignant on repeat aspiration (0.4 percent) [92,93]. In a third report, 3 of 216 patients (1.4 percent) had papillary cancer on a repeat biopsy [95].

Malignancy is rare even in benign thyroid nodules that have grown [48,97,98]. Cystic degeneration and hemorrhage are the most common causes of sudden enlargement and can be detected by ultrasonography or repeat aspiration [31]. In a prospective Italian study of the natural history of thyroid nodules, 992 mild to moderately iodine-deficient patients (without apparent risk factors for thyroid cancer) with 1567 nodules were monitored with yearly thyroid ultrasound for five years [48]. Nodular growth and nodule shrinkage occurred in 15.4 and 18.5 percent of patients, respectively. Among the 630 nodules (40.2 percent) that were classified as benign based on cytologic findings, only four nodules were subsequently found to be papillary thyroid cancer. Two of the four nodules were re-aspirated due to growth. However, the remaining two nodules were re-aspirated because of the appearance of suspicious ultrasound features, not growth.

A retrospective study assessed the growth rate of 126 malignant thyroid nodules followed for at least six months (mean 21 months) prior to surgery compared with 1363 benign nodules and found that 26 percent of malignant and 12 percent of benign nodules grew by more than 2 mm per year, with the relative risk (RR) of malignancy increasing from 1.85 to 5.05 for growth rates of more than 2 mm to more than 8 mm per year, respectively [99].

●Frequency of ultrasound imaging – The appropriate interval for ultrasound monitoring is uncertain as there are few studies that examine this issue. In a retrospective cohort study of 1369 patients with 2010 cytologically benign nodules, followed for an average of 8.5 years, there were no deaths attributable to thyroid illness or thyroid cancer [100]. Among the 325 patients who subsequently underwent thyroidectomy despite initially benign cytology, 45 (14 percent) had surgery because of abnormal cytology obtained on a repeat FNA biopsy of the same nodule (performed because of growth). Eighteen false-negative FNA results (1.3 percent) were confirmed (16 papillary, one follicular, one poorly differentiated cancer), and the mean time from initial benign cytology to thyroidectomy in these patients was 4.5 years. None of the patients had distant metastatic disease, and all were alive with no recurrence over a mean follow-up period of 11 years. This study, along with the prospective Italian study [48], suggests that less frequent monitoring of cytologically benign nodules may be warranted.

Symptomatic benign nodules — For symptomatic or cosmetically concerning benign nodules, we suggest surgery (typically lobectomy). Where expertise is available, ultrasound-guided ablation techniques are an alternative.  

Surgery has been the preferred treatment for symptomatic benign nodules. It is effective, but it is expensive and may be associated with complications. Surgical complications are lower when surgery is performed by surgeons with expertise in thyroid surgery [101] and when the extent of resection is limited (lobectomy versus total thyroidectomy). (See "Thyroidectomy", section on 'Complications'.)

Benign nodules can also be treated by ultrasound-directed physical energy (eg, radiofrequency ablation, laser ablation, microwave ablation, high-intensity focused ultrasound). While these approaches are utilized in Europe and Asia, they have not previously gained widespread acceptance in the United States. However, expertise in these techniques is developing, and many academic centers have set up programs for radiofrequency ablation of benign nodules (confirmed by two benign FNA results or one benign FNA result and a spongiform or predominantly cystic appearance on ultrasound) [102,103].

In a systematic review and network meta-analysis of 16 studies (3 randomized trials and 13 comparative case series) evaluating thermal ablation techniques or conventional surgery to treat benign thyroid nodules, thyroidectomy was associated with the largest reduction in thyroid volume compared with thermal ablation techniques but a higher risk of postoperative complications (eg, laryngeal nerve damage) and hypothyroidism [104]. There was no difference among the thermal ablation techniques in volume reduction, symptom score, or cosmetic score. The relatively short-term follow-up (mean 11.9 months) limited the evaluation of recurrent nodules. There were no trials comparing thyroid lobectomy with any thermal ablation technique.

In prospective studies, ultrasound-guided ablative procedures for benign, symptomatic nodules reduce volume size (mean reduction at six months 67 to 86 percent) and improve thyroid specific quality-of-life scores [105-107]. Adverse effects may include pain during and after the procedure and hematoma. Recurrent laryngeal nerve damage (often transient), skin burns, and tracheal injury have also been reported [107,108]. Treatment efficacy improves as clinicians increase their proficiency with the procedures. In one study, the efficacy of radiofrequency ablation (as assessed by the volume reduction ratio and ablation ratio) improved for cases 31 to 60 compared with the first 30 cases; further improvement in ablation ratio for smaller nodules was noted for cases 61 to 90 compared with cases 31 to 60, suggesting the learning curve continues beyond the first 60 cases [109].

Indeterminate cytology (Bethesda III and IV) — When cytologic results show atypia of undetermined significance (AUS) or follicular neoplasm, the results are often called indeterminate. The evaluation and management of nodules with indeterminate cytology, including the application of molecular markers, is reviewed separately. (See "Evaluation and management of thyroid nodules with indeterminate cytology in adults".)

Suspicious for malignancy (Bethesda V) — This category includes lesions with some features suggestive of, but not definitive for, papillary thyroid cancer, or other malignancies. Typically, nodules in this category have a 67 to 83 percent risk of malignancy or noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP, formerly called noninvasive follicular variant of papillary thyroid cancer but subsequently reclassified as a benign variant) (see "Papillary thyroid cancer: Clinical features and prognosis", section on 'Variant forms') [91]. Such patients should be referred for surgery. Molecular markers should not be used for this category; however, the results of mutational analysis may be helpful when the choice between lobectomy and total thyroidectomy is uncertain. (See "Evaluation and management of thyroid nodules with indeterminate cytology in adults", section on 'Molecular markers'.)

Malignant (Bethesda VI) — The malignant category includes papillary cancer, medullary thyroid cancer (MTC), thyroid lymphoma, anaplastic cancer, and cancer metastatic to the thyroid. Patients with cytology diagnostic of malignancy should be referred for surgery. (See "Differentiated thyroid cancer: Surgical treatment".)

For biopsy-proven papillary microcarcinoma confined to the thyroid with no cervical nodes or high-grade features, active surveillance is an alternative to surgery, especially for patients with other comorbidities who are at increased surgical risk [47,110,111]. However, if the recommendations for FNA noted above are followed, the preoperative diagnosis of papillary microcarcinoma should be a rare event. (See 'Sonographic criteria for FNA' above.)

Nondiagnostic (Bethesda I) — A nondiagnostic biopsy is cytologically inadequate. It is critical that the absence of malignant cells not be interpreted as a negative biopsy if no or scant follicular tissue is obtained. For patients with nondiagnostic FNA biopsies, we repeat the FNA in approximately four to six weeks, using ultrasound guidance if not used for the first FNA. In a study of patients with a nondiagnostic cytology specimen after a palpation FNA, repeating the FNA under ultrasound guidance significantly improved the diagnostic yield for both solid and cystic nodules [112].

If repeated ultrasound-guided aspirations are nondiagnostic, ultrasound-guided core-needle biopsy should be considered. In one study of patients who had one nondiagnostic FNA, a core-needle biopsy provided diagnostic results in 74 percent of patients, while a repeat FNA provided a result in only 52 percent of patients; after two nondiagnostic FNAs, the core needle provided a result in 86 versus 29 percent for FNA [113].

Surgical excision, especially for larger, solid nodules with sonographically suspicious features (table 2) [114], or observation, especially for smaller, partially cystic nodules, are reasonable options for repeatedly nondiagnostic biopsies. If growth of the solid component of the nodule (>20 percent in two dimensions on ultrasound) is detected during observation, diagnostic surgery is also reasonable.

In a study of 2234 consecutive FNAs, 352 (16 percent) were nondiagnostic. Among nondiagnostic nodules, 42 percent were nondiagnostic on a second FNA and 68 percent on a third FNA attempt. While not all nondiagnostic nodules were excised, papillary thyroid cancer was diagnosed in 8 percent [115].

Autonomous nodules — The optimal therapy of patients with autonomous nodules is controversial. Those in whom the nodule causes hyperthyroidism should be treated with radioiodine, surgery, or long-term antithyroid drugs. For patients who prefer to avoid radioiodine or surgery, ultrasound-guided thermal ablation procedures are an option (if centers with expertise are available). (See "Treatment of toxic adenoma and toxic multinodular goiter".)

Patients with subclinical hyperthyroidism (low serum TSH and normal serum free thyroxine [T4] values) present a difficult problem. Subclinical hyperthyroidism is associated with an increased risk of atrial fibrillation in patients over age 60 to 65 years and, in postmenopausal women, a decrease in bone mineral density (BMD). Management depends upon clinical risk for complications of subclinical hyperthyroidism and the degree of TSH suppression. This topic is reviewed in detail elsewhere. (See "Subclinical hyperthyroidism in nonpregnant adults".)

Cystic thyroid nodules — Cystic nodules also present difficult management issues. Many patients with small cystic nodules with nondiagnostic cytology can be followed with the assumption that the nodule is benign. In some patients, however, recurrent bleeding or cyst reformation may be a source of discomfort, anxiety, or rarely obstructive symptoms. Management is reviewed in more detail separately. (See "Cystic thyroid nodules", section on 'Management'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Thyroid nodules and cancer".)

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 AND RECOMMENDATIONS

●Initial evaluation – The initial evaluation in all patients with a thyroid nodule (discovered either by palpation or incidentally noted on a radiologic procedure, such as carotid ultrasonography, neck or chest computed tomography [CT], or positron emission tomography [PET]) includes a history, physical examination, neck ultrasonography, and measurement of serum thyroid-stimulating hormone (TSH) (algorithm 1). (See 'Evaluation' above.)

•TSH low – Thyroid scintigraphy should be performed in patients with a subnormal serum TSH concentration. (See 'TSH low' above and 'Thyroid scintigraphy' above.)

•TSH normal or elevated – If the serum TSH concentration is normal or elevated and the nodule meets sonographic criteria for sampling (table 3 and table 4), ultrasound-guided fine-needle aspiration (FNA) biopsy should be performed; a palpation FNA biopsy may be performed if ultrasound is not available (algorithm 1). FNA biopsy is the most accurate method for evaluating thyroid nodules and selecting patients for thyroid surgery. Nodules that do not meet sonographic criteria for FNA should be monitored. The frequency of evaluation depends upon the sonographic features of the nodules. (See 'TSH normal or high' above and 'Monitoring of nodules that do not meet FNA criteria' above.)

●Sonographic criteria for FNA – Thyroid nodules are selected for FNA based on suspicious ultrasonographic characteristics rather than size alone, as the presence of suspicious ultrasound features is more predictive of malignancy. (See 'Sonographic criteria for FNA' above.)

•Since active surveillance is considered safe for many papillary microcarcinomas, we generally do not biopsy highly suspicious (TR5) nodules under 10 mm. However, since active surveillance is not recommended for papillary microcarcinoma with certain high-risk features, we consider FNA (if achievable) in any TR5 nodule (regardless of size) with these suspicious sonographic features: subcapsular locations adjacent to the recurrent laryngeal nerve or trachea, extrathyroidal extension, extrusion through rim calcifications, or associated with abnormal lymph nodes.

•FNA should be performed in nodules that are solid and hypoechoic if they are ≥1.5 cm (as determined by largest dimension). FNA should be performed in nodules that are solid and hypoechoic if they are ≥1 to 1.5 cm with one of these suspicious sonographic features: irregular margins (≥1.5 cm), microcalcifications (≥1 cm), taller-than-wide shape (≥1 cm), macrocalcifications (≥1.5 cm), peripheral (rim) calcifications (≥1.5 cm).

•Nodules with sonographic appearance suggesting a low risk for thyroid cancer can be biopsied when larger (≥2.5 cm) (table 3 and table 4).

•Spongiform nodules can be observed without FNA.

●FNA technique – FNA biopsy of thyroid nodules is most commonly performed under ultrasound guidance. Ultrasound-guided FNA biopsy should always be performed for nonpalpable nodules and for nodules that are technically difficult to aspirate using palpation methods alone, such as predominantly cystic or posteriorly located nodules. In patients with large nodules (>4 cm), ultrasound-guided FNA directed at several areas within the nodule may reduce the risk of a false-negative biopsy. (See 'FNA technique' above and "Thyroid biopsy", section on 'Ultrasound guidance'.)

●Management

•Benign cytology – Patients with benign nodules (macrofollicular or adenomatoid/hyperplastic nodules, colloid adenomas, nodular goiter, and Hashimoto's thyroiditis) are usually followed without treatment. (See 'Surveillance' above.)

We perform periodic ultrasound monitoring of benign thyroid nodules initially at 12 to 24 months, then at increasing intervals (eg, three to five years), with the shorter intervals for large nodules or nodules with worrisome ultrasound features and the longer interval for smaller nodules with classic benign ultrasonographic features.

We repeat the FNA within 12 months if the initial ultrasound shows highly suspicious ultrasound features despite a benign biopsy. Repeat FNA is also warranted when there is substantial growth (more than a 50 percent change in volume or 20 percent increase in at least two nodule dimensions), there is the appearance of suspicious ultrasound features, or new symptoms are attributed to a nodule.

For symptomatic or cosmetically concerning benign nodules, we suggest surgery (typically lobectomy) (Grade 2C). Where expertise is available, ultrasound-guided ablation techniques are an alternative. (See 'Symptomatic benign nodules' above.)

•Indeterminate cytology – The evaluation and management of nodules with indeterminate cytology (atypia of undetermined significance [AUS] or follicular neoplasm), including the application of molecular markers, is reviewed separately. (See "Evaluation and management of thyroid nodules with indeterminate cytology in adults".)

•Suspicious for malignancy or malignant – Patients with nodules that are suspicious for malignancy or malignant should be referred for surgery. (See 'Suspicious for malignancy (Bethesda V)' above and 'Malignant (Bethesda VI)' above.)

•Nondiagnostic cytology – For patients with nondiagnostic palpation or ultrasound-guided biopsies, we perform repeat FNA using ultrasound guidance. For patients with solid nodules and nondiagnostic cytology after repeated biopsies, we typically perform an ultrasound-guided core-needle biopsy. Careful clinical follow-up, repeat FNA biopsy, and surgical resection are alternative options. For cytologically nondiagnostic nodules that are predominately cystic, we suggest careful clinical follow-up with ultrasound monitoring rather than surgical resection (Grade 2C). (See 'Nondiagnostic (Bethesda I)' above and "Cystic thyroid nodules".)