Aetiology

Intrathyroidal hyperplastic/neoplastic: euthyroid benign

Colloid nodules are the most common type of thyroid nodule. These are benign overgrowths of thyroid tissue with cystic colloid.

Thyroid adenomas are solid benign neoplasms and arise from the follicular epithelium within the thyroid gland. Morphologically they tend to be homogeneous, solitary, well-encapsulated tumours that demonstrate microfollicles, as opposed to hyperplastic nodules, which have normal- to large-sized follicles filled with abundant colloid, and lack a true histological capsule.

The presence of multiple colloid nodules, hyperplastic nodules, or thyroid adenomas leads to formation of non-toxic multinodular goitre.

Sudden enlargement of thyroid adenomas and hyperplastic nodules can be caused by haemorrhage within the nodule. This often leads to acute pain. This diagnosis should be considered in thyroid-nodule patients who are on anticoagulants or antiplatelet agents, or following blunt trauma to the anterior neck. When there is a substernal component to the goiter, this may rarely present with airway or thoracic symptoms. The differential diagnosis of a rapidly enlarging thyroid mass should also include anaplastic thyroid cancer and thyroid lymphoma.

Intrathyroidal hyperplastic/neoplastic: hyperthyroid benign

Autonomously hyper-functioning thyroid nodules are referred to as toxic adenomas. These have been referred to as 'hot nodules' because of their increased uptake of radioactive iodine on a nuclear scan, and they carry a low chance of malignancy.[3]​ Most hyper-functioning nodules have acquired somatic mutations in the thyroid-stimulating hormone (TSH)-receptor signalling pathway that cause an increase in TSH-independent nodular function and thyroid hormone production.[10]​ Multiple autonomously functional nodules lead to toxic multinodular goitre.

Intrathyroidal neoplastic: malignant

Differentiated thyroid cancers include papillary and follicular cancer.

  • Papillary thyroid cancer is the ​most common type of thyroid cancer, accounting for approximately 90% of all thyroid malignancies.[11]​ Most papillary cancers are identified in the early stages and carry an excellent prognosis.

  • Follicular thyroid cancer is not diagnosed through fine needle aspiration (FNA) biopsy because the distinction between benign and malignant follicular neoplasms rests on evidence of invasion into vessels, invasion through the capsule of the nodule, or invasion into adjacent structures, typically visible only on permanent (not frozen section) histology.

Medullary thyroid cancer arises from parafollicular cells, or C cells, in the thyroid gland. The tumour cells usually produce calcitonin, and measurement of calcitonin levels is used for pre-operative diagnosis, prognostication for cure or control of the disease, and for surveillance after surgery.[12] The tumour occurs in both sporadic and hereditary forms, the latter making up about 25% of the total.[12][13] The hereditary forms include familial medullary thyroid cancer and multiple endocrine neoplasia syndromes 2A and 2B, and are associated with mutations in the RET oncogene.

Anaplastic thyroid cancer constitutes <2% of all thyroid carcinomas.[14]​ It is composed of undifferentiated cells and is very aggressive.[14]​ Invasion of surrounding structures, such as the skin, muscles, nerves, vessels, larynx, and oesophagus, is common and distant metastases occurs early in the course of disease.[14]​​

Primary thyroid lymphomas account for 1% to 5% of all thyroid tumours and 2.5% to 7% of all extranodal lymphomas.[15]​ Primary thyroid lymphoma occurs in patients who usually have a history of chronic lymphocytic thyroiditis (Hashimoto's thyroiditis), and differentiating the two cytologically may be difficult.

Congenital/developmental/anatomical

Thyroid cysts are secondary to congenital, developmental, or neoplastic causes. Many cysts result from intranodular ischaemia causing tissue necrosis and liquefaction. True epithelial-lined cysts are rare.[16]

FNA is not necessary if a nodule is purely cystic because of the low malignant potential of such lesions; however, if they grow in size and cause symptoms, they may be aspirated in an effort to decompress them. Aspiration can be followed by ethanol ablation to prevent their recurrence.[1][2][17]

Pure cystic lesions should be differentiated from cystic variant papillary thyroid cancer. Cystic variant papillary cancers are usually partially solid rather than purely cystic lesions. The solid portions of such lesions may demonstrate the typical sonographic features associated with papillary thyroid cancer and should be biopsied.[1]​​[2][18]

Thyroglossal duct cysts are a common cause of midline neck masses. These can be found at any level from the base of the tongue to the isthmus of the thyroid gland, and most (65%) are infrahyoid in location.[19]​​

Infectious/inflammatory/autoimmune

Acute suppurative thyroiditis is very rare and occurs as a result of bacterial infection of the thyroid, most commonly arising in the presence of a patent branchial cleft remnant from the piriform sinus, which creates a conduit from the thyroid to the oropharynx.[20]​​

Subacute granulomatous thyroiditis is also known as de Quervain thyroiditis, 'painful' thyroiditis, or viral thyroiditis. Many viruses have been implicated in its pathogenesis, including mumps virus, Coxsackie viruses, influenza viruses, and echoviruses.[21]

Chronic lymphocytic thyroiditis (Hashimoto's thyroiditis) is a result of autoimmune destruction of the thyroid parenchyma and can occasionally lead to thyroid enlargement. Persistent destruction of thyroid parenchyma can lead to overt hypothyroidism at a rate of 2% to 4% a year in euthyroid patients with detectable thyroid autoantibodies.[22] It is the leading cause of hypothyroidism and the cause of diffuse thyroid enhancement on a positron emission tomography scan.[23]​ Its aetiology is posited to arise from the gut-thyroid axis and may stem from food allergies or intestinal dysbiosis.[24][25][26]​​​

Painless lymphocytic thyroiditis, which occurs most often in the postpartum period but may also occur sporadically, starts with an initial hyperthyroid phase, followed by subsequent hypothyroidism and, finally, a return to the euthyroid state.[27]​ Clinically it is differentiated from chronic lymphocytic (Hashimoto's) thyroiditis by the duration of the hypothyroid phase. Hypothyroidism associated with chronic lymphocytic thyroiditis is usually permanent but is self limited in painless lymphocytic thyroiditis with resolution generally within 6 months.

Graves' disease, an autoimmune disease characterised by antibodies against the TSH receptor (thyroid-stimulating immunoglobulin), is the most common cause of hyperthyroidism. Graves' disease typically leads to diffuse thyroid enlargement without development of thyroid nodules. Thyroid nodules and Graves' disease may co-exist.[28]​​ Patients with Graves' disease and co-existing thyroid nodules are more likely to be diagnosed with thyroid carcinoma than those without nodules.[29]

Non-thyroidal

Enlarged parathyroid glands may rarely be mistaken for thyroid nodules. They may occur as intrathyroidal masses or be so closely attached to the thyroid that distinction from thyroid tissue may be difficult, even with ultrasonography.

Parathyroid gland enlargement may be due to a parathyroid adenoma or parathyroid hyperplasia resulting from secondary or tertiary hyperparathyroidism as a consequence of chronic kidney disease and chronic and severe vitamin D deficiency.[30]​ Parathyroid carcinoma is a rare condition present in <1% of all patients with parathyroid disorders; however, it is more likely to cause a palpable neck mass than benign primary hyperparathyroidism.[31]

Metastasis of non-thyroidal cancers to the thyroid occurs infrequently with an incidence of 0.36% in all thyroid malignant tumours; however, the incidence of metastatic disease in the thyroid gland in autopsy reports is between 1.9% and 24%, indicating that thyroid metastatic cancer is often missed and misdiagnosed in the clinic.[32] ​The common primary sites that can produce thyroid metastases are the breast, lung, colon, and kidney.[32]​​

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