Thyroid nodules in adults are very common in clinical practice and most of them are benign lesions that do not require special management. The clinical management of thyroid nodules is focused on identifying benign and malignant nodules and excluding thyroid cancer. The malignancy rate of thyroid nodules ranges from 7-15% depending on age, gender, history of radiation exposure, family history, and other risk factors. The incidence of differentiated thyroid cancer (DTC) has been on a dramatic rise in recent years.
Overview of thyroid nodules
A thyroid nodule is a discrete lesion within the thyroid gland that is radiologically distinct from the surrounding parenchymal portion of the thyroid gland. Some palpable lesions do not correspond to significant abnormalities on imaging, and such abnormalities are not strictly defined as thyroid nodules.
Typically, thyroid nodules >1 cm in size are clinically significant for cancer risk and should be evaluated. A small number of nodules <1 cm also require further evaluation when combined with suspicious symptoms, associated lymph nodule enlargement, or other clinical high-risk conditions, such as a history of head and neck radiation in early childhood or a family history of thyroid cancer in a first-degree relative.
Nodules smaller than 1 cm have the potential to progress to tumor and even cause death, even if not supported by ultrasonography and clinical warning signs, but this rarely occurs. Considering the cost-effectiveness of healthcare, the risks of treating all small thyroid nodules as suspected thyroid cancer would far outweigh the benefits of the diagnosis.
In short, the majority of thyroid nodules have a low risk of malignancy, and most thyroid cancers pose a minimal health risk and can be effectively treated.
In healthy people with a family history of follicular cell carcinoma of the thyroid, routine screening is beneficial for early diagnosis of the disease. However, there is no evidence that ultrasound screening can reduce the incidence and mortality of thyroid cancer. Therefore, the guidelines are neutral on routine ultrasound screening in the healthy population.
Screening and follow-up of thyroid nodules
1.Serum thyroid stimulating hormone (TSH)
Patients with thyroid nodules should first have a serum TSH test.
If TSH is below normal, a thyroid nuclear scan should be performed.
If TSH is normal or high, an immediate thyroid nuclear scan is not recommended.
2.Serum thyroglobulin (Tg)
Tg is not a sensitive, specific indicator of thyroid cancer and is elevated in most thyroid diseases. Routine screening for Tg is not recommended for patients with thyroid nodules.(Strongly recommended, moderate quality evidence)
3. Serum calcitonin
The guidelines are neutral on the need for routine testing of serum calcitonin in patients with thyroid nodules, and neither recommend nor oppose it. (Insufficient evidence)
4. Ultrasound-confirmed thyroid nodules
If there is focal uptake to 18FDG-PET, suggesting an increased risk of thyroid cancer, fine needle aspiration biopsy is recommended for nodules larger than 1 cm of them. (Strongly recommended, moderate quality evidence)
If 18FDG-PET shows diffuse uptake, coupled with ultrasound and clinical evidence of chronic lymphocytic thyroiditis, no further imaging or fine-needle aspiration is required. (Strongly recommended, moderate quality evidence)
5. Ultrasound of the thyroid
Ultrasound of the thyroid and cervical lymph nodes should be performed in all patients with known or suspected thyroid nodules. (Strongly recommended, high quality evidence)
6. Ultrasound (US)-guided fine needle aspiration (FNA) of the thyroid
FNA is the recommended method for the evaluation of thyroid nodules as long as the indications for clinical application are met. (Strongly recommended, high quality evidence)
However, thyroid FNA is not recommended in the following cases.
a. nodules with a maximum diameter of <1 cm on ultrasound or ultrasound suggestive of very low risk of malignancy; (strong recommendation, moderate quality evidence)
b. Pure cystic nodules. (strongly recommended, moderate quality evidence)
7. Fine needle aspiration cytology of the thyroid
Diagnostic thyroid FNA cytology reports should be issued based on the Bethesda reporting system for thyroid cytopathology. (Strongly recommended, moderate quality evidence)
If cytology of the thyroid nodule is benign, no additional diagnostic testing and treatment is required immediately. (Highly recommended, high quality evidence)
If the cytologic findings are of primary thyroid malignancy, surgery is usually recommended. (Strongly recommended, moderate quality evidence)
Surgical treatment and histopathologic diagnosis should be considered for nodules that are not diagnosed on multiple cytologic examinations, if they are combined with ultrasound high-risk presentations, or if the nodule continues to increase in size (more than 20% increase in diameter) during ultrasound monitoring, or if clinical risk factors for malignancy are present. (Weak recommendation, low quality evidence)
8. Several special cytological findings
a. Follicular lesions of undetermined significance / atypical lesions (AUS/FLUS)
For AUS/FLUS cytology findings, FNA or molecular testing should be repeated to further assess the risk of nodal malignancy after reference to clinical and ultrasound adverse features as an alternative to long-term surveillance or diagnostic surgery. Individual patient wishes and feasibility should be taken into account in clinical decision making. (Weak recommendation, moderate quality evidence)
If FNA cytology and/or molecular testing is not repeated, or if the results are inconclusive, long-term surveillance or surgical resection of thyroid nodules with AUS/FLUS should be performed based on clinical risk factors, ultrasound morphology, and the patient’s personal preference. (Strongly recommended, low quality evidence)
b. Follicular tumors/suspicious follicular neoplasms (FN/SFN) of the thyroid
Diagnostic surgical resection has long been the standard management of FN/SFN cell nodules. However, in combination with clinical and ultrasound features, nodal malignancy risk assessment by molecular testing can also be performed as an alternative to direct surgery. Clinical decisions should also take into account individual patient wishes as well as feasibility. (Weak recommendation, moderate quality evidence)
If molecular testing is not performed, or if the results are inconclusive, the FN/SFN nodule should be surgically removed and a definitive diagnosis made. (Strongly recommended, low-quality evidence)
c. Suspicious of malignancy (SUSP)
If papillary carcinoma is suspected on cytology, surgical treatment with the same malignant cytology should be performed based on clinical risk factors, ultrasound features, patient’s wishes, and mutation testing results. (Strongly recommended, low quality evidence)
For SUSP thyroid nodules, mutation testing for BRAF or 7-gene mutation marker groups (BRAF, RAS, RET/PTC, PAX8/PPARγ) may be considered if mutation testing results are expected to alter surgical decision making, in combination with clinical and ultrasound features. (Weak recommendation, moderate quality evidence)
Routine 18FDG-PET is not recommended for the assessment of benignity or malignancy in nodules whose nature is not clarified by FNA cytology (AUS/FLUS, FN, SUSP). (weak recommendation, moderate quality evidence)
9. Thyroid nodules whose nature is not clearly defined by cytology
When considering surgery for a solitary nodule whose nature is not clearly defined by cytology, the preferred procedure is partial thyroidectomy. With appropriate adjustments based on clinical or ultrasound features, individual patient preference, and molecular test results. (Strongly recommended, moderate quality evidence)
For nodules of undetermined nature with suspected malignancy on cytology, total thyroidectomy should be preferred due to the elevated risk of malignancy, especially for specific tumors with known mutations, suspicious ultrasound patterns, large diameter (>4 cm), presence of radiation exposure or family history of thyroid cancer in the patient. Total thyroidectomy is recommended for unspecified malignant nodules remaining after partial thyroidectomy. (Strongly recommended, moderate quality evidence)
If nodules of undetermined nature are present in bilateral thyroid nodules, total thyroidectomy may be indicated for patients with significant comorbidities, or who prefer to undergo bilateral thyroidectomy to avoid the possibility of future repeat surgery. (Weak recommendation, low quality evidence)
10. Evaluation of multiple thyroid nodules
Having multiple >1 cm thyroid nodules is evaluated in the same way as having only a single >1 cm thyroid nodule. Considering that each >1 cm nodule is independently at risk for malignancy, patients with multiple nodules need to undergo FNA. (Strongly recommended, moderate quality evidence)
In the presence of multiple >1 cm nodules, the nodule with suspicious ultrasound morphology should be punctured first. FNA is preferred based on the ultrasound morphology and size of the different nodules. (Strongly recommended, moderate quality evidence)
If there are no nodules with suspicious ultrasound morphology, suggesting a very low probability of malignancy, puncture may be performed only for the largest nodules (>2 cm) or long-term ultrasound follow-up may be maintained without the need for FNA. (Weak recommendation, low quality evidence)
Serum TSH concentrations below normal or at the lower limit of normal suggest the possible presence of spontaneous nodules. At this point, a thyroid nuclear scan may be considered and compared with ultrasound images to determine the function of each >1 cm nodule. FNA should be considered for nonfunctional nodules, where nodules with highly suspicious ultrasound morphology are preferred. (weak recommendation, low quality evidence)
11.Thyroid fine needle aspiration molecular testing
Depending on the use of the test, molecular markers can be classified into diagnostic (classification of disease states), prognostic or predictive target categories (information on the possible benefit or risk of a particular treatment). For clinical applications, molecular testing should be performed in a CLIA/CAP-accredited molecular laboratory or other international equivalent, with assurance of test quality as a primary consideration. (Strongly recommended, low quality evidence)
When performing molecular testing, patients should be informed of the potential benefits of the test, its limitations, and the uncertainty in guiding treatment and long-term clinical significance. (Strongly recommended, low-quality evidence)
12. Follow-up of benign nodules on FNA cytology
For nodules with high ultrasound suspicion, ultrasound should be reviewed or ultrasound-guided FNA performed within 12 months.(Strongly recommended, moderate quality evidence)
For nodules with low to moderate ultrasound suspicion, ultrasound should be repeated in 12-24 months. If there are changes in ultrasound morphology (at least two nodules that are 20% larger and at least 2 mm larger or more than 50% change in volume), or if new suspicious ultrasound patterns appear, FNA should be repeated or follow-up ultrasound should be performed continuously to observe morphologic changes. (Weak recommendation, low quality evidence)
For ultrasound of very low suspicious nodules (including spongy nodules), the interval of ultrasound follow-up should be greater than two years. (No weak recommendation, inadequate low-quality evidence)
If repeat ultrasound-guided fine-needle aspiration is performed and both results are benign, no further ultrasound monitoring of the nodule for risk of malignancy is required. (Strong recommendation, moderate quality evidence)