The thyroid specialist frequently evaluates thyroid nodules because they may represent malignancy. Nodules are typically found on physical examination or incidentally when other imaging studies are performed. Malignant or symptomatic nodules that compress nearby structures warrant surgical excision. Yet, the majority of thyroid nodules are asymptomatic and benign, so the thyroid surgeon must rely on diagnostic studies to determine when surgery is indicated. Ultrasound is the preferred imaging modality for thyroid nodules, and the ultrasound guided fine-needle aspiration biopsy (FNAB) is the preferred method of tissue sampling. Nodules 1 cm or larger or nodules with suspicious sonographic appearance warrant cytologic analysis to better quantify the risk for malignancy. Molecular biomarkers are a powerful adjunct to cytology. Detecting malignancy preoperatively allows total thyroidectomy in a single operation without the need for frozen section or a second operation for completion of a thyroidectomy if malignancy is found during the initial thyroid lobectomy.
The thyroid nodule is a common entity. Although autopsy data indicate a 50% prevalence of thyroid nodules larger than 1 cm in patients without clinical evidence of thyroid disease, the prevalence of palpable nodules is only 4% to 7%. Ultrasonography is far more sensitive than palpation because it detects nodules of any size in up to 67% of the general population. Thyroid nodules warrant removal when they are large enough to be symptomatic or if there is a concern for malignancy. The majority of nodules are asymptomatic, and with only 5% to 10% of nodules being malignant, the decision to operate is made on therapeutic or diagnostic grounds. Ultrasound imaging studies and cytology from fine-needle aspiration (FNA) are the main tools used by the clinician to decide whether surgical excision of a thyroid nodule is warranted. Molecular genetic biomarker analyses are now being used to increase the accuracy of fine-needle aspiration biopsies (FNAB), and appear to substantially alter the clinical decision-making process as they become more widely available and more thoroughly evaluated.
Clinical assessment
Patients most often present with a large palpable nodule in the neck or report of an incidental nodule found on imaging studies performed for another reason. A single dominant or solitary nodule is more likely to represent carcinoma than a single nodule within a multinodular gland, with an incidence of malignancy from 2.7% to 30% and 1.4% to 10% respectively. Yet, the overall risk for malignancy within a gland with a solitary nodule is approximately equal to that of a multinodular gland because of the additive risk of each nodule. Important elements in patients’ history that increase the likelihood of malignancy include prior head and neck irradiation (especially during childhood, with a relative risk of 8.7 at 1 Gy for X rays and gamma radiation); reports of rapid growth, dysphagia, dysphonia, male gender, presentation at extremes of age (less than 20 years or more than 70 years); and a family history of medullary thyroid carcinoma or multiple endocrine neoplasia.
Physical examination findings that increase the concern for malignancy include
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Nodules larger than 4 cm in size (19.3% risk of malignancy)
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Firmness to palpation
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Fixation of the nodule to adjacent tissues
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Cervical lymphadenopathy
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Vocal fold immobility.
Physical examination may be limited by patients’ body habitus and an inherent variation between physicians and their assessment of nodules such that more precise measurements are obtained through imaging. Positive predictive values of 100% for thyroid malignancy in the setting of a nodule have been reported for the physical examination findings of cervical lymphadenopathy (greater than 1 cm) and vocal fold immobility. Assessment of a patient’s voice is not adequately sensitive at detecting vocal fold immobility when compared with flexible laryngoscopy. A thorough head and neck examination with visualization of vocal fold movement is therefore of utmost importance on initial presentation.
Laboratory studies
Most patients presenting with a solitary thyroid nodule are euthyroid, and the simplest way to verify this is a serum thyrotropin (TSH) level. If below normal, the workup proceeds with total or free thyroxine (T4) and total triiodothyronine (T3) to better evaluate the hyperthyroid state. This result occurs in approximately 10% of patients with a solitary thyroid nodule and is suggestive of a benign hyperfunctioning adenoma. Serum calcitonin levels should be obtained in any patient with a family history of medullary thyroid carcinoma, multiple endocrine neoplasia types 2a or b, pheochromocytoma, or hyperparathyroidism. Because only 1 in 250 nodules represent medullary thyroid carcinoma, serum calcitonin testing is reserved for high-risk patients. Furthermore, calcitonin levels alone are unable to distinguish between benign and malignant disease.
Laboratory studies
Most patients presenting with a solitary thyroid nodule are euthyroid, and the simplest way to verify this is a serum thyrotropin (TSH) level. If below normal, the workup proceeds with total or free thyroxine (T4) and total triiodothyronine (T3) to better evaluate the hyperthyroid state. This result occurs in approximately 10% of patients with a solitary thyroid nodule and is suggestive of a benign hyperfunctioning adenoma. Serum calcitonin levels should be obtained in any patient with a family history of medullary thyroid carcinoma, multiple endocrine neoplasia types 2a or b, pheochromocytoma, or hyperparathyroidism. Because only 1 in 250 nodules represent medullary thyroid carcinoma, serum calcitonin testing is reserved for high-risk patients. Furthermore, calcitonin levels alone are unable to distinguish between benign and malignant disease.
Imaging studies
Ultrasonography
Ultrasonography is the imaging study of choice for thyroid nodules. It can identify nodules too small to be palpated, the presence of multiple nodules, central or lateral neck lymphadenopathy, and provides accurate measurements of nodule diameter for interval monitoring. Additionally, it allows characterization of nodules by sonographic features that suggest malignancy. Solid appearance (or hypoechogenicity); increased vascularity; microcalcifications;, irregular margins; and the absence of a halo are features that have been consistently associated with malignancy ( Table 1 ). There is certainly some subjectivity to these features, and characteristics vary depending on the histology such that ultrasound alone cannot reliably distinguish malignant and benign lesions. Although they do not obviate the need for biopsy, these features are extremely useful in selecting the site within a nodule for FNAB to improve diagnostic yield or to select appropriate nodules to aspirate within a multinodular thyroid.
| Median Sensitivity (%) | Median Specificity (%) | |
|---|---|---|
| Microcalcifications | 52 | 83 |
| Absence of halo | 66 | 54 |
| Irregular margins | 55 | 79 |
| Hypoechoic | 81 | 53 |
| Increased intranodular flow | 67 | 81 |
Radioisotope Imaging
Radioisotope scanning can be used to determine if a thyroid nodule is functioning but it does not provide an accurate measurement of size. Radioisotopes that have been used are technetium ( 99m Tc), 123 I, and 131 I, and though similar information is obtained with similar amounts of radiation exposure, radioiodine is preferred. About 80% to 85% of thyroid nodules are cold, and about 10% of these nodules represent a malignancy. Hot nodules account for 5% of all nodules, and the likelihood of malignancy is less than 1% for these nodules. Taken together, the sensitivity for the diagnosis of thyroid cancer is 89% to 93%, specificity is 5%, and the positive predictive value of malignancy is only 10%. Except for obviating the need to perform an FNAB on a hyperfunctioning nodule in patients who are thyrotoxic, the use of radioisotope scanning has been nearly abandoned in the initial workup of a thyroid nodule.
CT and MRI
Both of these imaging modalities have almost no role in the initial evaluation of a thyroid nodule and are rarely indicated in the initial workup. However, they are both excellent (100% sensitivities) for evaluating the extent of large substernal goiters that may be compressing nearby structures. Iodinated contrast material utilized for CT scan should be avoided because its use prevents scintigraphy or administration of radioactive iodine therapy for a period of 1 to 2 months. Gadolinium contrast used with MRI does not interfere with thyroid uptake of radiotracer, but it is significantly more expensive than CT or ultrasound.
18 F-fluorodeoxyglucose Positron Emission Tomography-CT
18 F-fluorodeoxyglucose positron emission tomography-CT ( 18 FDG-PET/CT) is used extensively in oncology for staging, evaluation of treatment response, and detecting recurrences on the principle that malignant cells have a higher uptake of 18 FDG because of increased metabolic demands when compared with normal tissues. Generally, the appearance of the images and maximum standard uptake value (SUV max ) can be used to distinguish between malignant and benign lesions. This does not appear to be the case with thyroid nodules because there is no significant difference in SUV max between benign and malignant 18 FDG-avid nodules. Some have suggested that 18 FDG-PET/CT may play a role in reducing the need for diagnostic thyroid lobectomy for FNAB indeterminate lesions because it has negative predictive values 95% to 100%. Although such preliminary studies are promising, further research is needed before observation could universally be recommended over surgery for non- 18 FDG–avid thyroid nodules with indeterminate FNA cytology. Although 18 FDG-PET/CT does not play a role in the workup of a nodule, any 18 FDG-avid thyroid nodule found incidentally deserves a thorough workup for malignancy.
FNAB
FNAB is the most important step in the workup of the thyroid nodule, as cytology is the primary determinant in whether thyroidectomy is indicated. FNAB is widely available and well tolerated, with a low risk for complications. Its use has dramatically decreased the number of thyroidectomies performed and improved the yield of malignancy in glands that have been extirpated. FNAB can be performed with or without ultrasound guidance, but diagnostic accuracy is improved using sonographic needle localization because of a decreased number of inadequate specimens and false-negative results.
The pathology report from FNAB may be read as benign, malignant, indeterminate, or nondiagnostic. The exact terminology may vary between institutions as there is currently no standard means of reporting FNAB cytology specimens, especially with regard to indeterminate specimens. The latest proposal from the National Cancer Institute is that cytology should universally be reported under six categories that more accurately predict the risk for malignancy ( Table 2 ). Benign lesions on FNAB have an approximate 3% risk for malignancy (although this will vary with patient population), and may be followed clinically with ultrasound or with a repeat FNAB which, if also benign, decreases the risk for a false negative to 1.3%.
| Proposed Categories | Risk of Malignancy (%) |
|---|---|
| Benign | <1 |
| Follicular lesion of undetermined significance | 5–10 |
| Neoplasm (follicular or oncocytic) | 20–30 |
| Suspicious for malignancy | 50–75 |
| Malignant | 100 |
| Nondiagnostic | N/A |
The only malignant pathology reliably diagnosed through FNA is papillary thyroid carcinoma because features, such as Orphan Annie nuclei, nuclear grooves, intranuclear inclusions, and psammoma bodies, can be sufficient for a diagnosis. Medullary carcinoma, anaplastic carcinoma, lymphoma, poorly differentiated carcinoma, and metastatic disease have also been reported to be classified on the basis of cytology. Benign and malignant follicular neoplasms and oncocytic (formerly called Hurthle cell) adenomas and carcinomas cannot be distinguished on the basis of cytology alone, because tissue architecture is required to make the diagnosis of malignancy through observation of capsular or angiolymphatic invasion. Although this has historically been true, recent advances in the application of molecular markers to FNAB are changing these principles.
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