The article was written by Assoc. Prof. M. Siderova and Prof. K. Hristozov
Nodular goiter is a heterogeneous disease in clinical, physiological and histological aspects: nodules can be single or multiple, accompanied by hyper- or hypofunction, benign or malignant. The main tasks of the clinician in the detection of nodular goiter are the exclusion of malignancy and of hyperthyroidism due to thyroid autonomy.
Epidemiology
Thyroid nodules are detected in approximately 5% of the population using palpation as a screening method. When ultrasound screening is performed, this percentage increases tenfold and reaches between 20 and 75% of the general population. A higher incidence of thyroid nodules is seen in areas endemic for goiter. Thyroid nodules are rare in children and adolescents, and their incidence increases linearly with age. Women are affected 2-4 times more than men.
Thyroid carcinoma is a rare human malignancy, accounting for up to 1% of malignancies, but is the most common endocrine cancer. It is found in about 5% of thyroid nodules. Over the last 30 years, the annual incidence of thyroid carcinoma has increased from 6 to 8.7/100,000, i.e. 2.4 times. This increase is thought to be largely due to improved diagnosis and the increase has been at the expense of diagnosing nodules less than 2 cm, with the mortality rate from thyroid carcinoma unchanged at 0.5/100,000. The accident in
Chernobyl in 1986 marked a new era in the incidence of thyroid cancer. The risk of developing thyroid cancer, especially in Ukraine, Belarus, western Russia and neighbouring countries, was greatest for children who were then under 9 years of age and especially under 5 years of age and had probably ingested a large dose of radioactive iodine through milk and dairy products. An increasing number of thyroid carcinoma cases are expected in Japan in the coming years following the Fukushima accident.
Clinical Evaluation
From the history, the most important information is the sex (men- they are at higher risk for malignant lesions), as well as the age of onset of the nodule. Risk age groups are those under 20 years and over 70 years. Past radiotherapy to the head and neck is also a risk factor. Dysphonia, dysphagia and dyspnoea as well as rapid growth of the nodule are alarming symptoms. Familiality should also be sought, especially in relatives with medullary, papillary carcinoma u MEN type 2 (multiple endocrine neoplasia). Symptoms of hyperthyroidism as well as use of medications containing iodine may suggest toxic nodular goiter. Most nodules are asymptomatic and the absence of symptoms does not rule out malignancy.
Physical examination of the neck is mandatory, focused on the size, localization, consistency of the thyroid nodule, fixation to the surrounding tissues, the presence of neck pain, as well as enlarged cervical lymph nodes (LNs).
Laboratory examination
Most patients with benign or malignant thyroid nodules are euthyroid. However, serum TSH testing is appointed in all patients with a thyroid nodule. If the TSH is low, laboratory tests are expanded to include FT4 and FT3, which clarify whether it is overt (with elevated peripheral hormones) or subclinical hyperthyroidism (normal peripheral hormones combined with low TSH). In both cases, scintigraphy is appropriate to determine functional nodal activity. Most guidelines do not recommend scintigraphic hot node biopsies because they are rarely malignant. In high TSH, testing for FT4, anti-TPO, and anti-TG antibodies is indicated because autoimmune thyroiditis is the most common cause of hypothyroidism.
The serum thyroglobulin test has no place in the diagnosis of nodular goiter, since it is elevated in any gland enlargement, as well as in destructive changes. Its use as a tumor marker in patients treated for thyroid carcinoma makes sense only after a total thyroidectomyl has been performed.
The serum calcitonin assay is a marker for medullary carcinoma and correlates well with disease prevalence. Its routine measurement in the presence of a thyroid nodule is still controversial, as medullary carcinoma is found in less than 0.5% of nodules, and serum calcitonin is often false-positive in renal insufficiency or use of proton inhibitors. Its investigation is due in familial or clinical suspicion of medullary carcinoma or MEN type 2. If calcitonin is elevated, it is first repeated, followed by a stimulation test with pentagastrin or calcium.
Ultrasound diagnostics
Ultrasound (US) examination is the most sensitive method for the detection of thyroid nodules, to accurately determine their size and structure. Ultrasonography is mandatory in patients with clinically established risk of thyroid carcinoma, in cervical lymphadenomegaly and in any palpable nodule. In 20% to 48% of patients with a single palpable nodule, other nodules are detected sonographically, i.e., polynodous stroma. The risk of carcinoma is the same in patients with a solitary nodule and a multinodular goiter. Moreover, carcinoma may lie in the dominant node (the one with the largest size) as well as in the nondominant ones.
The focus of the US examination in nodular goiter is to look for features at risk for malignancy - hypoechogenic solid nodule structure, uneven contours, lack of halo, anterior-posterior greater than transversal size, microcalcifications, intravascular chaotic Doppler signals, cervical lymphadenomegaly.
Elastography is another application of U3 to study the deformation and elasticsp of tissues in compression. The nodes or parts of nodes that deform minimally, i.e. are rigid and inelastic, are at risk.
There are also some ultrasonographic features suggestive of a benign nature of the nodule - clear borders, the presence of gentle continuous halo, dorsal acoustic enhancement, hyper- or anechogenic nodule structure, and the presence of eggshell-type macrocalcifications. Very often the pseudonodous form of Hashimoto's autoimmune thyroiditis is confused with polynodous goiter .
Fine-needle aspiration biopsy (FNA) is the most accurate and important diagnostic method to differentiate benign from malignant thyroid nodules. Routine performance of FNA has changed the management of thyroid nodules by avoiding unnecessary surgery of benign lesions and thus reducing the cost of treatment. On the other hand, preoperative FNA and demonstration of thyroid carcinoma implies a single-stage operation, total thyroidectomy, in contrast to multiple operations in patients without preoperative cytological clarification. The sensitivity of FNA ranges between 65% and 98% and the specificity between 72% and 100%. There are different methods of performing FNA - with and without aspiration, "free hand", and FNA under ultrasonographic control, the latter having advantages in nonpalpable nodules as well as in the choice of the biopsy site from solid-cystic nodulesl.
Cytology results from TAB are classified into five diagnostic categories:
Class 1. Nondiagnostic
Reasons for insufficient cytological material can be very small nodules, poor in epithelial cells and erythrocyte-rich sample, poor fixation, sclerotic lesions (Hashimoto's thyroiditis-fibrosing variant), cystic degeneration of the node, necrosis. In case of one non-diagnostic result of TAB, it should be repeated. In case of a second non-diagnostic TAB of a solid nodule, most authors recommend surgical removal of the nodule. This decision is also influenced by the ultrasonographic characteristics, size and dynamics in nodule growth.
Class 2. Benign
In case of a benign cytological result, the patient is followed clinically, c TSH u US at 6 to 18 months. Repeat FNA is recommended when clinical or US features suggestive of malignancy occur or when nodule volume increases more than 50% from baseline. Suppressive levothyroxine treatment of benign nodules used in the past is not routinely recommended because of its low efficacy and nonbeneficial cardiovascular and bone effects. Indications for surgical treatment of benign thyroid nodules are compression syndrome, previous external irradiation, rapid growth, susceptible U3 features, and cosmetic considerations. The extent of resection for a single nodule is lobectomy with ischemectomy, and for a multinodular goiter is near-total thyroidectomy. Alternatives to surgical treatment are percutaneous ethanol sclerosant, laser ablation, and high-frequency ultrasound (H1FU) ablation. Radioiodine therapy (RIA) is the treatment of choice for hyperfunctioning and/or symptomatic nodules in patients with high operative risk. Follow-up of patients after RYL for stromal nodosis includes thyroid function testing (TSH, FT3, FT4) and U3 every 3-6 months, and RIA can be repeated in cases of persistent hyperthyroidism or insufficient volume reduction in compressive manifestations.
Class 3. Folicular nodules
Repeat biopsy is not recommended for this category of nodules, as cytological examination cannot differentiate follicular adenoma from follicular carcinoma (respectively Hurthle cell adenoma from carcinoma). Differentiation requires histological verification of capsular and/or vascular invasion. Several molecular markers (Galectin-3, Cytokeratin-19, Fibronectin, Claudin, HBME1) have been identified that have different expression in benign and malignant thyroid nodules. Their immunocytochemical study in FNA material could increase the sensitivity and specificity of routine cytological examination. Most guidelines recommend operative removal of all follicular lesions.
Class 4. Suspicious
Patients with diagnostic category 4-specific thyroid nodules are referred for surgical treatment. For these nodules, intraoperative geographic examination is also recommended.
Class 5. Malignant
Surgical removal is mandatory in case of a malignant cytological result. Preoperatively, a good US view or CT scan for cervical lymph nodes is necessary. In the case of a suspected metastatic LNs, thyroglobulin or calcitonin in the smear from the needle used to perform the FNA of the LNs can be tested along with its cytology. CT/MRI is indicated in selected cases to determine invasion of the trachea and surrounding structures.
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