Thyroid nodules are very common, and the prevalence of thyroid nodules in our population is 10.2 to 18.6%. The prevalence is lower in men than in women. The prevalence increases significantly with age, with the highest prevalence of thyroid nodules in the age group above 60 years. Most of the thyroid nodules are benign, and malignant nodules account for only 5% to 10% of thyroid nodules.
1. Medical history and signs
The majority of patients with thyroid nodules have no clinical symptoms and are often detected by physical examination or by their own touch or imaging. A detailed history and comprehensive physical examination can help in the diagnosis of thyroid nodules. The history should focus on the patient’s age, gender, history of head and neck radiation exposure, detailed questions about changes and growth rate of thyroid nodules, history of neck pain, hoarseness, dyspnea, history of palpitations, excessive sweating, hand tremors and indifference, swelling, etc. The history of thyroid disease and its family history should also be noted. The physical examination should focus on the number, size, texture, mobility of the nodules, the presence of pressure pain, and the presence of enlarged lymph nodes in the neck.
The key to the diagnosis and management of thyroid nodules is the differentiation between benign and malignant lesions. Clinical evidence suggesting that thyroid nodules may be malignant is as follows: (1) history of head and neck radiation exposure in childhood or adolescence; (2) family history of medullary thyroid cancer or type 2 multiple endocrine neoplasm; (3) age less than 20 years or more than 70 years; (4) male; (5) enlarged nodules; (6) recent voice changes, abnormal swallowing or breathing; (7) hard, irregularly shaped, poorly mobile nodules; (8) with neck lymph node enlargement.
The following four conditions have the same likelihood of malignant thyroid nodules: isolated thyroid nodules, multinodular goiter, clinically palpable nodules, and accidental thyroid nodules (i.e., incidental tumors). In addition, available data suggest that small thyroid nodules are as invasive as large thyroid nodules and can invade the thyroid envelope and surrounding lymph nodes, so it is not considered that the size of the nodule is an indicator of its invasiveness.
2.Serological examination
(1) Thyroid function tests: Most patients with thyroid nodules have serum thyroid hormone and thyroid stimulating hormone (TSH) levels within the normal range. Although only a very small number of patients with thyroid malignancy have abnormal thyroid function, serum TSH and thyroid hormone levels must be measured in all patients with definite thyroid nodules.
(2) Thyroglobulin level (TG) measurement: elevated TG is seen in thyroid nodules of all causes. In patients with benign nodular goiter, serum TG is normal or elevated; after T4 treatment the nodules subside and serum TG decreases. In patients with multinodular goiter, serum TG is normal or elevated. TG increases with nodule enlargement and decreases with iodine supplementation. There is no significant difference between the TG level of thyroid cancer patients and other diseases, and the detection of TG is not significant for the diagnosis of thyroid cancer. However, by observing the dynamic changes of TG, it is beneficial for the early detection of postoperative residual, recurrence and metastasis of differentiated thyroid cancer. For patients with thyroid and 131I debridement, TG level measurement has high specificity and sensitivity.
(3) Thyroid autoantibody tests: positive thyroid stimulating antibody (TSAB) suggests Graves’ disease; positive iodine transporter antibody does not support the diagnosis of thyroid malignancy; other antibodies such as thyroglobulin antibody (TGAB) and thyroid peroxidase antibody (TPOAB) are measured without special clinical significance for differentiating benign from malignant, but are useful for diagnosing Hashimoto’s thyroiditis, especially for patients with elevated serum TSH.
(4) Measurement of calcitonin levels: Patients with thyroid nodules have significantly elevated serum calcitonin levels, which can help in the early diagnosis of medullary thyroid cancer. Serum calcitonin levels are positively correlated with tumor size. In patients with a family history of medullary thyroid carcinoma or type 2 multiple endocrine neoplasia, serum calcitonin levels should be measured in the basal or stimulated state. However, the current study concluded that it is not recommended as a routine test for patients with thyroid nodules.
3.Imaging examination
(1) Thyroid ultrasound: Ultrasound is one of the imaging methods of choice in the examination of thyroid nodule-like lesions. Two-dimensional and color Doppler ultrasound have important clinical applications for the diagnosis and differential diagnosis of thyroid nodules. Thyroid ultrasonography is mandatory for all patients suspected of having thyroid nodules. Thyroid ultrasonography can determine the nature of the nodule, differentiate between cystic and solid lesions, and perform ultrasound-guided fine needle aspiration and cytology (FNAC) of the thyroid gland when necessary. The report should include the location, morphology, size, number of nodules, state of the nodule margins, internal structure, echogenicity, blood flow and cervical lymph nodes. When ultrasonography cannot make a benign or malignant diagnosis of thyroid nodules, the ultrasonographer should palpate the nodules directly, noting the nodule borders, mobility, texture, and the presence of enlarged lymph nodes around the nodules and in the neck. Clinical examination is very helpful for the correct diagnosis of thyroid lesions by ultrasound. Cases in which the diagnosis of benign or malignant is difficult to make on sonography should be combined with clinical examination.
Currently, high-resolution thyroid ultrasonography is the most sensitive method to evaluate thyroid nodules. Features of high-resolution thyroid ultrasonography that suggest malignant nodules include: (1) microcalcifications; (2) irregular nodule margins; and (3) disturbance of blood flow in the nodule. All three have a high specificity of more than 80%, but a low sensitivity of 29% to 77.5%, suggesting malignant lesions in nodules. Therefore, one feature alone is not sufficient to diagnose malignant lesions. However, if two or more features are present at the same time, or if a hypoechoic nodule is combined with one of these features, the sensitivity of the diagnosis of malignant lesions increases to 87%-93%. The malignancy of a nodule is independent of the size of the nodule, whether it is single or multiple, or whether it is combined with a cystic lesion.
The application of real-time ultrasound elastography (UE) provides a stronger basis for the diagnosis and differential diagnosis of thyroid nodules, which is a new technique for imaging the mechanical characteristics of tissue, based on the difference in stiffness between the lesion and the tissue, and its own elastic properties, and the information it obtains is an important complement to conventional ultrasound. The sensitivity of conventional ultrasound and elastography combined to diagnose malignant thyroid nodules is 73,33%, the specificity is 88,37%, and the accuracy is 89,66%.
The use of ultrasonography has helped to improve the detection rate of tumors. This technique involves the injection of contrast agent through a peripheral vein, which causes a large amount of microbubble contrast agent to be suspended in the blood and increases the acoustic impedance difference between the blood and the gas, thus enhancing the backscatter of the microbubbles, resulting in an enhanced echo signal at the site and improving the signal-to-noise ratio of the echo. The contrast agent can visualize parenchymal organs such as the thyroid and liver, which in turn can observe the state of tissue perfusion and enhance the display of tumor microvessels. Zhao Ying et al [18] found that the contrast enhancement pattern of malignant thyroid nodules is mostly diffuse overall enhancement, and benign nodules are mostly peripheral before internal enhancement and predominantly peripheral circumferential enhancement, with slight or always no internal enhancement.
(2) CT and MRI of the thyroid gland: CT scan and MRI are valuable in helping to detect nodules and understand the size, number, location and enlargement of lymph nodes, but they cannot determine the nature of nodules and are not routinely used in clinical practice. CT and MRI of the thyroid gland are mainly used for retrosternal thyroid nodules and can evaluate tracheal compression.
(3) PET can distinguish between benign and malignant, but it is expensive, not available in general units, and cannot replace biopsy, so it is not recommended.
4.Cytological examination
Fine needle aspiration cytology biopsy (FNAC) of the thyroid gland is the most reliable and valuable diagnostic method to distinguish benign and malignant nodules. The literature reports that its sensitivity is 83%, specificity is 92%, and accuracy is 94%. The results of FNAC are: (1) benign lesions; (2) malignant lesions; (3) junctional lesions; and (4) undiagnostic. fnac has a clear diagnostic value in identifying various thyroid nodules. Preoperative FNAC examination helps to clarify the cytological type of cancer before surgery and determine the correct surgical plan. The FNAC test can clearly diagnose papillary thyroid cancer, medullary thyroid cancer, undifferentiated carcinoma, Hashimoto’s thyroiditis, subacute thyroiditis, septic thyroiditis, cystic thyroid lesions, parathyroid cysts, etc. parathyroid cysts, etc. It is important to note that the FNAC test cannot differentiate between follicular carcinoma and follicular cell adenoma of the thyroid.
FNAC may fail due to failure to obtain a satisfactory specimen. Reasons for failure may include unskilled handling, low cell count or no cells at all in the specimen, inexperienced or poorly skilled pathologists, and diluted or cystic fluid specimens. Preoperative education can effectively reduce patients’ nervousness and anxiety and alleviate their pain, thus improving puncture efficiency, shortening puncture time and reducing puncture failure.
In recent years, with the development of ultrasound-guided FNAC, the accuracy rate of FNAC has been greatly improved. At present, most authoritative guidelines have clear requirements and indications for ultrasound-guided FNAC, namely, the following seven conditions can be guided by ultrasound: (1) nodules >1 cm, but not palpable; (2) nodules <1, 5 cm, palpable; (3) deep thyroid nodules; (4) nodules adjacent to blood vessels; (5) cystic or mixed nodules; (6) traditional FNAC cannot diagnose (6) nodules that cannot be diagnosed by conventional FNAC; (7) coexistence of hard-to-reach lymph nodes.
5.Thyroxine scan
A thyroid nuclear scan is usually performed using I123 and I131 imaging. It is characterized by the ability to evaluate the function of the nodules. The nodules are classified as “hot nodules”, “warm nodules” and “cold nodules” according to their ability to take up radionuclides. “Hot nodules” account for 10% of nodules and “cold nodules” account for 80% of nodules. Almost all of the “hot nodules” are benign lesions, and malignant lesions are very rare. The rate of malignancy in “cold nodules” is 5% to 8%. Therefore, if the thyroid nuclei are “hot nodules”, they are almost benign, and if the TSH is decreasing and the nuclei are confirmed to be high-functioning nodules, there is no need to perform FNAC. A “cold nodule” is not very helpful in determining the benignity or malignancy of a thyroid nodule. FNAC is indicated for patients with thyroid nodules in combination with hyperthyroidism and subclinical hyperthyroidism.
Thyroid 99TcmO-4/99Tcm
labeled methoxyisobutylisocyanide (99TcmO-4/99Tcm
2MIBI) combined imaging has improved the confirmation rate of malignant thyroid nodules, with a positive predictive value of 47,5%, but a good negative predictive value (96,9%), i.e., if the scan is negative, malignancy is highly unlikely.
6.Gene testing and tumor markers
In recent years, it has been a popular research to identify and determine the specific tumor markers to identify benign and malignant thyroid nodules and estimate the prognosis. Application of molecular biology can detect BRAF gene mutation in punctured cells, and if the mutation is detected, papillary adenocarcinoma can be identified. It has been reported that in 10-16% of cases that cannot be identified by conventional cytology, the application of genetic tests can lead to a correct diagnosis RET genetic screening is also important for immediate relatives of families with medullary thyroid cancer or endocrine syndrome MEN2A and 2B for early detection of microscopic medullary carcinoma or as a basis for prophylactic thyroidectomy in family members. The common tumor markers are matrix metalloproteinases (MMPs), anti-human leukocyte antigen monoclonal antibody system (CD), human Tg, epidermal growth factor (EGF), transforming growth factor (TGF), and galectin-3. However, no ideal tumor marker has been found so far to verify the nature of thyroid nodules.