Thyroid nodules are a common clinical condition. The palpation rate is approximately 6% in women and 2% in men. High-resolution ultrasound can detect thyroid nodules in up to 76% of the population. Most nodules are benign or cystic, with about 5% to 10% being malignant tumors. A small proportion of thyroid nodules function autonomously to secrete thyroid hormones.
Etiology
The etiology and pathogenesis are still unclear. Benign thyroid nodules include multinodular goiter, thyroid cysts, follicular adenomas, Hürthle cell adenomas, as well as nodules formed in conditions such as Hashimoto’s thyroiditis and subacute thyroiditis. Malignant nodules are mostly thyroid carcinomas; a small number are primary thyroid lymphomas or metastatic cancers.
Clinical Presentation
Most thyroid nodules are asymptomatic and are often detected during routine physical exams or imaging studies. Symptoms related to thyroid dysfunction may occur if thyroid function is abnormal. Nodules can cause compressive symptoms, leading to cough or shortness of breath if the trachea is compressed, or difficulty swallowing if the esophagus is compressed. Retrosternal thyroid nodules may result in Pemberton’s sign. Local invasion of surrounding tissues suggests the possibility of malignancy. Hoarseness may occur with recurrent laryngeal nerve involvement, hemoptysis may occur with tracheal invasion, and distant metastasis of thyroid cancer may present with symptoms such as chest pain, respiratory difficulty, bone pain, or neurological deficits.
Risk factors for thyroid cancer in nodules include:
- History of head and neck radiation exposure during childhood.
- Family history of medullary thyroid carcinoma, multiple endocrine neoplasia type 2 (MEN2), or papillary thyroid carcinoma.
- Age under 14 years or over 70 years.
- Male.
- Rapid nodule growth.
- Irregular, hard, or fixed nodules.
- Suspicious cervical lymphadenopathy.
- Persistent hoarseness, difficulty speaking, difficulty swallowing, or difficulty breathing.
Laboratory Tests
Thyroid function tests are typically the first step. When TSH levels are decreased, a thyroid radionuclide scan (e.g., 99mTcO4-, 123I, or 131I) helps determine whether the nodule is autonomously hyperfunctioning. Hyperfunctioning "hot" nodules have a very low risk of malignancy, and fine-needle aspiration (FNA) biopsy is generally unnecessary. For nodules with normal or elevated TSH, FNA is performed when ultrasound reveals malignant features. TPOAb and TgAb tests are useful for identifying autoimmune thyroiditis. Patients with a family history of medullary thyroid carcinoma or MEN2 should undergo serum calcitonin and carcinoembryonic antigen (CEA) testing. Serum thyroglobulin measurement cannot reliably differentiate between benign and malignant nodules.
Imaging Studies
Ultrasound is the most important imaging modality for evaluating thyroid nodules and has a higher diagnostic value for differentiating malignancy compared to CT or MRI. Ultrasound provides information about the location, size, number, composition (solid or cystic), echogenicity, morphology, calcification, margins, vascularity, and relationship of the nodule to adjacent structures, as well as the status of cervical lymph nodes. Risk stratification based on ultrasound features guides the need for FNA and further management. Features suggestive of malignancy include: solid composition, hypoechogenicity, taller-than-wide shape, microcalcifications, irregular margins, extrathyroidal extension, or abnormal cervical lymph nodes.
For nodules classified as intermediate- or high-risk (solid hypoechoic nodules with or without the above malignant features), FNA is recommended when the diameter is ≥1 cm. For low-risk nodules (solid iso- or hyperechoic nodules without the above malignant features), FNA is advised when the diameter is ≥1.5 cm. Extremely low-risk nodules (spongiform or partially cystic nodules without malignant features) are recommended for FNA only when the diameter is ≥2 cm. Advances in artificial intelligence (AI) technology have led to ongoing research on AI-based ultrasound systems to differentiate benign from malignant thyroid nodules.
CT or MRI of the neck is primarily used to evaluate the relationship between thyroid nodules and surrounding anatomical structures and to identify abnormal cervical lymph nodes. Radionuclide scanning mainly evaluates whether the nodule is autonomously hyperfunctioning. For nodules with 18F-FDG PET positivity, the malignancy risk is approximately 30% to 40%, limiting accuracy in distinguishing between benign and malignant nodules.
Fine-Needle Aspiration Biopsy
Ultrasound-guided fine-needle aspiration (FNA) biopsy is the current international standard for preoperative differentiation of benign and malignant thyroid nodules, with a sensitivity and specificity exceeding 90%. According to the Bethesda System for Reporting Thyroid Cytopathology, FNA cytology results are categorized into six groups:
- Category I: Non-diagnostic.
- Category II: Benign.
- Category III: Atypia of undetermined significance (AUS) or follicular lesion of undetermined significance (FLUS).
- Category IV: Follicular neoplasm or suspicious for follicular neoplasm.
- Category V: Suspicious for malignancy.
- Category VI: Malignant.
Nodules classified as Bethesda Categories III, IV, and V are considered cytologically indeterminate. Molecular testing may assist in further clarifying the diagnosis. Molecular testing primarily focuses on genetic mutations/rearrangements and mRNA expression. Tests identifying specific genetic mutations or rearrangements (e.g., BRAF, RAS, RET/PTC, PAX8/PPARG) tend to have a high positive predictive value. Genomic sequencing classifiers (GSC) and similar tests have high diagnostic sensitivity and negative predictive value, potentially reducing the rate of diagnostic surgeries for cytologically indeterminate nodules.
Diagnosis and Differential Diagnosis
The diagnosis of thyroid nodules requires a comprehensive evaluation considering medical history, clinical manifestations, laboratory tests, and thyroid ultrasound findings. Ultrasound-guided FNA provides an accurate assessment of nodule malignancy and enables differential diagnosis. For cytologically indeterminate nodules identified by FNA, molecular diagnostics can facilitate a more definitive diagnosis.
Treatment
Nodules that are highly suspected to be malignant based on clinical assessments or confirmed as malignant through FNA require surgical treatment.
Benign thyroid nodules require long-term follow-up and maintenance of adequate iodine intake. TSH suppression therapy is not recommended. Clinical or ultrasound findings suggesting malignancy, or significant nodule growth exceeding 50% in volume (or an increase in at least two dimensions by over 20% and greater than 2 mm), indicate the need for repeat ultrasound-guided FNA to confirm the diagnosis.
Surgical treatment is preferred for benign nodules causing compressive symptoms or those located in the retrosternal area, followed by postoperative levothyroxine (L-T4) replacement therapy. Autonomous hyperfunctioning thyroid nodules may be treated with surgery or radioactive iodine therapy.
For solid nodules measuring ≥2 cm in diameter that cause compressive symptoms or cosmetic concerns, ultrasound-guided thermal ablation therapy is an optional treatment. Prior FNA biopsy is required to confirm the nodule is benign before ablation. Thyroid cysts or predominantly cystic nodules (cystic component >90% of total volume) may be treated with ultrasound-guided percutaneous ethanol injection (PEI) or polidocanol injection (PLI).