Approach

The most common presentation is an asymptomatic thyroid nodule in women in their 30s or 40s.

Risk factors for thyroid cancer include a history of head and neck irradiation, which is a strong but uncommon factor. Thyroid cancer is more common in women, but men have a higher risk of malignancy in thyroid nodules.[29]

Rarely, thyroid cancer occurs as part of a familial syndrome such as a multiple endocrine neoplasia (MEN) syndrome. See Multiple endocrine neoplasia syndromes.

Examination and detection of thyroid nodule

A thyroid nodule might be found on physical examination or incidentally on imaging studies.

18F-FDG positron emission tomography/computed tomography (PET/CT)-positive thyroid nodules found incidentally may have a higher risk of malignancy and should be investigated appropriately.[12] Papillary thyroid carcinoma is the most common malignant histological type in this setting.[12][39]​​

Clinical examination may be unremarkable, or cervical lymphadenopathy may be palpable. Locally advanced cancer may present with hoarseness due to a paralysed ipsilateral vocal cord, or with dyspnoea or dysphagia. The trachea may be deviated to the opposite side, and the nodule itself may be firm to hard in consistency. Rapid neck enlargement is unusual, but suggests lymphoma (usually in the setting of Hashimoto's thyroiditis), haemorrhage into a nodule, or anaplastic thyroid cancer.[3][5][29]​​

Initial laboratory tests

Thyroid-stimulating hormone (TSH) level should be ordered initially.[1]​ If TSH is suppressed, thyroid hormone levels and a radioactive iodine scan are the next steps. The scan may identify a hyperfunctioning (hot) nodule, which is almost always benign.

If TSH is normal or elevated, the next diagnostic step is ultrasound and fine-needle aspiration (FNA) of the thyroid nodule.[1] 

Imaging studies and FNA

​An ultrasound should be performed in all patients with a thyroid nodule to confirm its presence, and assess size, location, and cystic component(s).[1][29][40][41] ​​​​​​Ultrasound evaluation of the cervical lymph nodes should also be performed.[1]​​[41][42]​​​

Most cystic nodules are in fact solid-cystic, for which the risk of malignancy is the same as for solid nodules. However, ultrasound can help to guide aspiration of any solid component. In multi-nodular goitres, FNA of cold (hypofunctioning) nodules should be performed based on features suspicious for malignancy rather than size.[29] FNA of thyroid nodules <1 cm is not recommended unless ultrasound findings are suspicious for malignancy or the patient has a high-risk history.[1][29]​

Ultrasound-based risk stratification systems can be used to inform decisions on when to perform an FNA.[11][43]​​[44]​ The American College of Radiology Thyroid Imaging, Reporting, and Data System (ACR TI-RADS) classifies nodules based on ultrasound features as benign, not suspicious, mildly suspicious, moderately suspicious, or highly suspicious for malignancy (TR1 to TR5).[11] See Classification section. Each risk stratification system has its own guidance on the threshold for FNA.

Reporting of cytology findings in FNA specimens

The Bethesda System for Reporting Thyroid Cytopathology (BSRTC) is commonly used to report FNA cytology findings, and is recommended by the American Thyroid Association.[1] The Bethesda system includes six diagnostic categories with an implied cancer risk that recommends the next clinical management step.[8]​ See Classification section.

Approximately 70% of thyroid nodules are benign, with only 5% to 10% reported as 'malignant', and with the remainder having an indeterminate diagnosis with risk of malignancy; for this last group, molecular testing is beneficial.[45]

Cytology may identify the thyroid cancer type.[46]​ However, for follicular or oncocytic neoplasms, cytology does not distinguish between adenoma (benign) and carcinoma.[47][48]​​​ In these cases, molecular testing or surgery (e.g., lobectomy) to look for capsular or vascular invasion is required to confirm a diagnosis.[29][49]​​​[Figure caption and citation for the preceding image starts]: Histopathology of follicular carcinoma, thyroidCDC Image Library/Dr Edwin P. Ewing, Jr [Citation ends].com.bmj.content.model.Caption@35b5403e[Figure caption and citation for the preceding image starts]: Histopathology of papillary carcinoma, thyroid: a psammoma body is visible (arrow)CDC Image Library/Dr Edwin P. Ewing, Jr [Citation ends].com.bmj.content.model.Caption@3c4d5a03

Additional tests to consider

Molecular testing of FNA specimens may be performed to detect genomic mutations/alterations (e.g., BRAF V600, MET, RET/PTC, NTRK, RAS, PAX8::PPARG) to enhance interpretation of indeterminate cytology findings (including follicular or oncocytic neoplasms) and to help guide treatment decisions (e.g., use of targeted therapies).[37]​ 

If FNA is suspicious for lymphoma, a core biopsy may be used for confirmation.[50] However, core biopsy is not recommended for the initial identification and evaluation of thyroid lesions.[51][52]

Serum calcitonin level should be checked if medullary thyroid carcinoma is confirmed or suspected (e.g., on cytology or when there is a family history suggestive of familial medullary cancer or a multiple endocrine neoplasia [MEN] syndrome).[4][37]​​​​ Genetic testing is required for patients with a family history of MEN syndromes or a cytological diagnosis of medullary thyroid cancer.[4][37]​​ Almost all patients with MEN type 2A (MEN2A), MEN2B, or isolated familial medullary thyroid cancer have germline RET (REarranged during Transfection) mutations, and around 50% of sporadic medullary thyroid cancers have somatic RET mutations.[4] Different types of RET mutation account for different biological behaviour and may guide future management (such as screening for, and treatment of, phaeochromocytoma and hyperparathyroidism).[53] RAS mutations are present in up to 23% of sporadic medullary thyroid cancer cases.[28] Patients with medullary cancer should undergo pre-operative neck imaging studies (ultrasound, CT) to evaluate cervical lymph node.[4]

Vocal cord mobility should be examined in patients with voice change/hoarseness.[1] Laryngoscopy, which may show a paralysed vocal cord, is recommended in patients with pre-operative voice abnormalities and in patients with gross extrathyroidal extension of cancer posteriorly or extensive nodal involvement, even if the voice is normal.[1]

Serum thyroglobulin is useful for post-treatment monitoring of papillary or follicular (including oncocytic) thyroid cancer, but not for diagnosis of thyroid malignancy. It is also useful for predicting future disease-free status before post-operative radioiodine therapy for remnant ablation, whereby low pre-ablation thyroglobulin levels may be considered a favourable risk factor in patients with differentiated thyroid cancer.[54]

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