A thyroid nodule is a discrete lesion within the thyroid gland that is palpably and/or ultrasonographically distinct from the surrounding thyroid parenchyma. However, some palpable lesions may not correspond to distinct radiologic abnormalities (14). Such abnormalities do not meet the strict definition for thyroid nodules. Other nonpalpable nodules are easily seen on ultrasound or other anatomic imaging studies, and are termed incidentally discovered nodules or "incidentalomas." Nonpalpable nodules have the same risk of malignancy as palpable nodules with the same size (15). Generally, only nodules larger than 1 cm should be evaluated, because they have the potential to be clinically significant cancers. Occasionally, there may be nodules smaller than 1 cm that require evaluation, because of suspicious ultrasound findings, a history of head and neck irradiation, or a positive family history of thyroid cancer.
With the discovery of a thyroid nodule, a complete history and physical examination focusing on the thyroid gland and adjacent cervical lymph nodes should be performed (Fig. 1). Pertinent historical factors predicting malignancy include a history of head and neck irradiation, total body irradiation for bone marrow transplantation (16), family history of thyroid carcinoma in a first-degree relative, exposure to fallout from Chernobyl under the age of 14 years (17), and rapid growth and hoarseness. Pertinent physical findings suggesting possible malignancy include vocal cord paralysis, ipsilateral cervical lymphadenopathy and fixation of the nodule to surrounding tissues.
FIG. 1. Algorithm for the evaluation of patients with one or more thyroid nodules. aIf the scan does not show uniform distribution of tracer activity, ultrasound may be considered to assess for the presence of a cystic component
Serum thyrotropin and imaging studies. With the discovery of a thyroid nodule larger than 1-1.5 cm in any diameter, a serum thyrotropin (TSH) level should be obtained. If the serum TSH is subnormal, a radionuclide thyroid scan should be obtained to document whether the nodule is functioning (i.e., has tracer uptake greater than the surrounding normal thyroid), isofunctioning or "warm" (i.e., has tracer uptake equal to the surrounding thyroid), or nonfunctioning (i.e., has uptake less than the surrounding thyroid tissue). Because functioning nodules rarely harbor malignancy, if one is found that corresponds to the clinical nodule, no additional cytologic evaluation is necessary. If overt or subclinical hyperthyroidism is present, additional evaluation is required.
R1. Measure serum TSH in the initial evaluation of a patient with a thyroid nodule—Recommendation C
Diagnostic thyroid ultrasound should be performed unless the serum TSH is suppressed. Thyroid ultrasound can answer the following questions: Is there truly a nodule that corresponds to the palpable abnormality? Is the nodule greater than 50% cystic? Is the nodule located posteriorly in the thyroid gland? These last two features might decrease the accuracy of fine needle aspiration biopsy performed with palpation (18,19). Also, there may be other thyroid nodules present that require biopsy based on their size and appearance (14,20,21). Even if the TSH is elevated, FNA is recommended because the rate of malignancy in nodules is similar in thyroid glands involved with Hashimoto's thyroiditis as in normal thyroid glands (22).
R2. Thyroid sonography should be performed in all patients with one or more suspected thyroid nodules—Recommendation B
Other laboratory testing:
Serum thyroglobulin measurement. Serum thyroglobulin levels can be elevated in most thyroid diseases and is an insensitive and nonspecific test for thyroid cancer (23).
R3. Routine measurement of serum thyroglobulin for initial evaluation of thyroid nodules is not recommended—Recommendation F
Serum calcitonin measurement. The utility of serum calcitonin has been evaluated in a series of prospective, nonrandomized studies (24-26). The data suggest that the use of routine serum calcitonin for screening may detect C-cell hyperplasia and medullary thyroid cancer at an earlier stage and overall survival may be improved. However, there remain unresolved issues of sensitivity, specificity, assay performance, and cost effectiveness. Furthermore, most studies rely on pentagastrin stimulation testing to increase specificity and this drug is no longer available in the United States. However, if the unstimulated serum calcitonin determination has been obtained and the level is greater than 100 pg/mL, medullary cancer is likely present (27).
R4. The panel cannot recommend either for or against the routine measurement of serum calcitonin—Recommendation I
FNA is the most accurate and cost effective method for evaluating thyroid nodules. Traditionally FNA biopsy results are divided into four categories: nondiagnostic, malignant, indeterminate or suspicious for neoplasm, and benign. Nondiagnostic biopsies are those that fail to meet specified criteria for adequacy that have been previously established (5). Such biopsies need to be repeated using ultrasound guidance (28). Some nodules, particularly those that are cystic, continue to yield nondiagnostic cytology results despite repeated biopsies, and may be malignant at the time of surgery (29,30).
R5. FNA is the procedure of choice in the evaluation of thyroid nodules—Recommendation A
R6. Cystic nodules that repeatedly yield nondiagnostic aspirates need close observation or surgical excision. Surgery should be more strongly considered if the cytologically nondiagnostic nodule is solid—Recommendation A
R7. If a cytology result is diagnostic of malignancy, surgery is recommended (31)—Recommendation A
Indeterminate cytology, often reported as "suspicious," "follicular lesion," or "follicular neoplasm," can often be found in 15%-30% of FNA specimens. While certain clinical features such as gender and nodule size (32) or cytologic features such as presence of atypia (33) can improve the diagnostic accuracy in patients with indeterminate cytology, overall predictive values are still low. Many molecular markers have been evaluated to improve diagnostic accuracy for indeterminate nodules (34,35) but none can be recommended because of insufficient data.
R8. At the present time, the use of specific molecular markers to improve the diagnostic accuracy of indeterminate nodules is not recommended—Recommendation I
R9. If the cytology reading is indeterminate (often termed "suspicious," "follicular lesion," or "follicular neoplasm"), a radioiodine thyroid scan should be considered, if not already done. If a concordant autonomously functioning nodule is not seen, lobectomy or total thyroidectomy should be considered—Recommendation B
R10. If the reading is "suspicious for papillary carcinoma or Hurthle cell neoplasm," a radionuclide scan is not needed, and either lobectomy or total thyroidectomy is recommended—Recommendation A (36)
R11. If the nodule is benign on cytology, further immediate diagnostic studies or treatment are not routinely required—Recommendation A
Patients with multiple thyroid nodules have the same risk of malignancy as those with solitary nodules (14,37). A diagnostic ultrasound should be performed to delineate the nodules, but if only the "dominant" or largest nodule is aspirated, the thyroid cancer may be missed (14). Sonographic characteristics are superior to nodule size for identifying nodules that are more likely to be malignant (37,38) and include the presence of microcalcifications, hypoechogenicity (darker than the surrounding thyroid parenchyma) of a solid nodule, and intranodular hypervascularity (37,38). The detection of microcalcifications and nodular vascularity has good interobserver reliability (39).
R12a. In the presence of two or more thyroid nodules larger than 1-1.5 cm, those with a suspicious sonographic appearance should be aspirated preferentially—Recommendation B
R12b. If none of the nodules has a suspicious sonographic appearance and multiple sonographically similar coalescent nodules are present, the likelihood of malignancy is low and it is reasonable to aspirate the largest nodules only—Recommendation C
R13. A low or low-normal serum TSH concentration may suggest the presence of autonomous nodule(s). A radioiodine scan should be performed and directly compared to the ultrasound images to determine functionality of each nodule larger than 1-1.5 cm. FNA should then be considered only for those isofunctioning or nonfunctioning nodules, among which those with suspicious sonographic features should be aspirated preferentially—Recommendation B
Thyroid nodules diagnosed as benign require follow-up because of a low, but not negligible, false-negative rate of up to 5% with FNA (40,41). While benign nodules may decrease in size, they often increase in size, albeit slowly (42). Nodule growth is not in and of itself an indication of malignancy, but growth is an indication for repeat biopsy. For nodules with benign cytologic results, recent series report a higher false negative rate with palpation FNA (1%-3%) (43-45) than with ultrasound FNA (0.6%) (44). In one study investigating the value of routine reaspirations of benign nodules, the nodule grew in the three patients who were subsequently found to have thyroid cancer (37). Because the accuracy of physical examination for nodule size is likely inferior to that of ultrasound (21), it is recommended that serial ultrasound be used in follow-up of thyroid nodules to detect clinically significant changes in size. There is no consensus on the definition of nodule growth, however, or the threshold that would require rebiopsy. Some groups suggest a 15% increase in nodule volume, while others recommend measuring a change in the mean nodule diameter (42,46). One reasonable definition of growth is a 20% increase in nodule diameter with a minimum increase in two or more dimensions of at least 2 mm. The false-negative rate for benign thyroid nodules on repeat FNA is low (47).
R14. Easily palpable benign nodules do not require sonographic monitoring, but patients should be followed clinically at 6-18 month intervals. It is recommended that all other benign thyroid nodules be followed with serial ultrasound examinations 6-18 months after initial FNA. If nodule size is stable, the interval before the next follow-up clinical examination or ultrasound may be longer—Recommendation B
R15. If there is evidence for nodule growth either by palpation or sonographically, repeat FNA, preferably with ultrasound guidance—Recommendation B
Evidence from multiple randomized control trials and three metaanalyses suggest that thyroid hormone in doses that suppress the serum TSH to subnormal levels may result in a decrease in nodule size in regions of the world with borderline low iodine intake. Data in iodine sufficient populations are less compelling (48-50).
R16. The panel does not recommend routine suppression therapy of benign thyroid nodules—Recommendation F
R17. Patients with growing nodules that are benign after repeat biopsy should be considered for continued monitoring or intervention with surgery based on symptoms and clinical concern—Recommendation C. There are no data on the use of levothyroxine in this subpopulation of patients—Recommendation I
Thyroid nodules in children. Thyroid nodules occur less frequently in children than in adults. In one study in which approximately 5000 children aged 11 to 18 were assessed annually in the southwestern United States, palpable thyroid nodules occurred in approximately 20 per 1000 children, with an annual incidence of 7 new cases per 1000 children (51). Some studies have shown the frequency of malignancy to be higher in children than adults, in the 15%-20% range (52-54), whereas other data have suggested that the frequency of thyroid cancer in childhood thyroid nodules is similar to that of adults (55,56). FNA biopsy is sensitive and specific in the diagnosis of childhood thyroid nodules (53-55).
R18. The diagnostic and therapeutic approach to one or more thyroid nodules in a child should be the same as it would be in an adult (clinical evaluation, serum TSH, ultrasound, FNA)—Recommendation A
Thyroid nodules in pregnant women. It is uncertain if thyroid nodules discovered in pregnant women are more likely to be malignant than those found in nonpregnant women (57), because there are no population-based studies on this question. The evaluation is the same as for a nonpregnant patient, with the exception that a radionuclide scan is contraindicated.
R19. For euthyroid and hypothyroid pregnant women with thyroid nodules, FNA should be performed. For women with suppressed serum TSH levels that persist after the first trimester, FNA may be deferred until after pregnancy when a radionuclide scan can be performed to evaluate nodule function—Recommendation A
If the FNA cytology is consistent with thyroid cancer, surgery is recommended. However, there is no consensus about whether surgery should be performed during pregnancy or after delivery. To minimize the risk of miscarriage, surgery during pregnancy should be done before 24 weeks' gestation (58). However, thyroid cancer discovered during pregnancy does not behave more aggressively than that diagnosed in a similar aged group of nonpregnant women (59,60). A retrospective study of pregnant women with differentiated thyroid cancer found there to be no difference in either recurrence or survival rates between women operated on during or after their pregnancy (60). Furthermore, retrospective data suggest that treatment delays of less than 1 year from the time of thyroid cancer discovery do not adversely effect patient outcome (61).
R20. A nodule with malignant cytology discovered early in pregnancy should be monitored sonographically and if it grows substantially (as defined above) by 24 weeks' gestation, surgery should be performed at that point. However, if it remains stable by midgestation or if it is diagnosed in the second half of pregnancy, surgery may be performed after delivery—Recommendation C
(Click to enlarge Fig. 1)