Approach

The Bethesda system for reporting thyroid cytopathology is widely used for preoperative assessment of fine-needle aspiration (FNA) specimens. It determines a diagnostic category based on tumor cytology, and each category has an implied cancer risk that recommends the next clinical management step.[8]​​ See Classification section.

Patients with thyroid cancer should be managed by a multidisciplinary team.

Differentiated thyroid cancer: papillary, follicular, or oncocytic

Treatment of differentiated (papillary, follicular, oncocytic [previously known as Hürthle cell]) thyroid cancer depends on the extent of identifiable disease and the risk that unidentifiable disease foci are also present.[14]

For patients with very low-risk tumors (e.g., unifocal papillary microcarcinomas [≤1 cm] with no evidence of extracapsular extension or lymph node metastases), active surveillance with ultrasound follow-up of the thyroid and neck lymph nodes every 6-12 months can be considered.[1]​​​​​​​​[37][66]​​​[74][75]​​​​ Guidance does not routinely recommend FNA for a cytologic diagnosis on nodules less than 1 cm with low-risk features; however, this policy varies internationally, with some countries performing FNA and cytology for suspicious nodules before offering active surveillance.[37][76]​​​​

Active surveillance may be the preferred option in older patients and those at high surgical risk.[1][74]​

Transitioning to surgery during active surveillance is indicated if the patient requests surgery or there are clinical changes (e.g., new biopsy-proven lymph node metastases; distant metastases; invasion into recurrent laryngeal nerve, trachea, or esophagus; radiologic evidence of extrathyroidal extension; cancer growth by 3 mm in any dimension or a 50% volume increase).[37][76]

For all other thyroid cancers, surgery is generally recommended for initial treatment.[1][37][74]​​ Total thyroidectomy is considered the standard surgical treatment. However, in patients with a tumor between 1 and 4 cm in diameter without extrathyroidal extension, and without clinical evidence of any lymph node metastases, lobectomy can be considered for the initial surgical procedure.[1] It is important that patients understand that intraoperative findings during lobectomy may necessitate completion of a total thyroidectomy (completion thyroidectomy).[1][37]

Completion thyroidectomy for follicular and oncocytic thyroid carcinomas

Surgery (e.g., total thyroidectomy or lobectomy) is required to confirm (histologically) a diagnosis of follicular or oncocytic carcinoma because FNA cytology does not reliably distinguish between follicular or oncocytic adenoma (benign) and carcinoma.[1][37]

If invasive follicular or oncocytic carcinoma is diagnosed following initial lobectomy, then subsequent completion thyroidectomy may be required depending on the invasiveness of the tumor.[1][37]

Completion thyroidectomy is required if a patient has invasive follicular or oncocytic carcinoma that is:[37]

  • widely invasive (gross invasion of the thyroid gland with or without adjacent soft tissues and blood vessels), or

  • encapsulated angioinvasive with involvement of ≥4 blood vessels.

Disease monitoring is typically preferred in a patient with invasive follicular or oncocytic carcinoma that is: minimally invasive (encapsulated tumor with microscopic capsular invasion and without vascular invasion), or is encapsulated angioinvasive with involvement of <4 blood vessels.[37] 

Differentiated thyroid cancer: postsurgical thyroid hormone replacement therapy

Total thyroidectomy necessitates thyroid hormone replacement therapy (e.g., levothyroxine). As circulating thyroid-stimulating hormone (TSH) stimulates proliferation in normal thyrocytes and most thyroid cancer cells, TSH-suppressive doses of thyroid hormone therapy are used.[14] The use of thyroid hormone suppression should be based on initial risk of disease and ongoing risk assessment of disease status (see Diagnostic criteria for risk stratification). The lowest possible amount of thyroid hormone should be used.[77]

  • In patients with high-risk disease, maintaining a serum TSH level of <0.1 mIU/L is recommended.[1] Maintaining a serum TSH level of <0.1 mIU/L (but not necessarily undetectable) is also recommended in patients with residual structural disease or a biochemically incomplete response if they are young or at low risk of complications such as exogenous subclinical hyperthyroidism.[37][77]

  • In patients with intermediate-risk disease, maintaining a serum TSH level of 0.1 to 0.5  mIU/L is recommended.[1]

  • In patients with low-risk disease, serum TSH levels should be maintained in the low to normal range (0.5 to 2.0 mIU/L).[1][74]

Patients with low-risk disease who have undergone lobectomy may not require thyroid hormone replacement therapy if their serum TSH is maintained in a low to normal target range.[1]

Differentiated thyroid cancer: complications of surgery and thyroid hormone replacement therapy

Complications of total thyroidectomy include an increased risk of recurrent laryngeal nerve damage or hypoparathyroidism.[1][37] The risk of permanent hypoparathyroidism is higher for total than for subtotal thyroidectomy. The patient should be referred to an experienced surgeon. 

TSH-suppressive doses of thyroid replacement therapy may result in exogenous subclinical hyperthyroidism, which in turn can result in adverse outcomes such as osteoporosis, fractures, and cardiovascular disease, including atrial fibrillation.[77] Bone loss is of particular concern for TSH suppression in postmenopausal, non-estrogen-treated women, but the effect of TSH suppression on fracture rate is unclear.[1][78]

Differentiated thyroid cancer: central neck dissection

Therapeutic central neck dissection for patients with clinically involved central nodes should accompany total thyroidectomy to provide clearance of disease from the central neck.[1]

Prophylactic central neck dissection is controversial.[74] In some centers it is recommended, but the reduction in locoregional recurrence is accompanied by an increased rate of postoperative adverse effects.[79]

Differentiated thyroid cancer: postsurgical radioactive iodine therapy

Risk assessment (based on surgical and pathologic findings) and assessment of postoperative disease status (including serum thyroglobulin [Tg] measurements and neck ultrasound) are required to guide selection of patients for radioactive iodine therapy.[1][54][80][81]

  • The use of radioactive iodine therapy is recommended following total thyroidectomy in patients with high-risk disease and in selected patients with intermediate-risk disease.[1][81]

  • Radioactive iodine therapy is not routinely recommended for patients with low-risk disease, but features that impact on recurrence risk, disease follow-up implications, and patient preferences should be considered.[1][82]

Selecting the optimal dose of therapeutic radioactive iodine can be challenging and should be based on risk assessment, and individualized (e.g., guided by patient factors and treatment goal).[1][37][81][80] Consult local guidance.

Radioactive iodine therapy encompasses three overlapping treatment goals.[80]

  • Remnant ablation: to destroy postoperatively residual, presumably benign thyroid tissue to facilitate initial staging and follow-up studies

  • Adjuvant treatment: to destroy subclinical tumors after surgery to lower the risk of recurrence and improve survival

  • Treatment of known biochemical or structural disease.

Increased TSH levels are required to induce radioactive iodine uptake in thyroid cells.[81] Administration of exogenous recombinant human TSH (rhTSH) is the preferred method of preparation for radioactive iodine therapy for most patients.[37] 

Following radioactive iodine therapy, a whole-body radioactive iodine scan should be obtained to stage the disease and document the radioactive iodine avidity of any structural lesions.[73]

Use of a "diagnostic" radioactive iodine scan following surgery, but before radioactive iodine therapy, is controversial.[81][80]​​ A diagnostic radioactive iodine scan may yield information relevant to clinical decision-making in selected patients only.[73] [Figure caption and citation for the preceding image starts]: Increased uptake of radioiodine in both pulmonary fields and the mediastinum due to miliary lung metastasis from papillary thyroid carcinomaGkountouvas A, Chatjimarkou F, Thomas D, et al. Miliary lung metastasis due to papillary thyroid carcinoma. BMJ Case Reports. 2009; doi:10.1136/bcr.06.2008.0322 [Citation ends].com.bmj.content.model.Caption@f44878e

Differentiated thyroid cancer: recurrence or metastatic disease

The risk of recurrence is determined at time of diagnosis and re-evaluated as a continuum in response to early therapies.[66] Serum thyroglobulin assays and neck ultrasound are the mainstays of differentiated thyroid cancer follow-up.[1][74]​ 

Recurrence may be biochemical or structural.

Management of patients who develop biochemical recurrence (i.e., rising or newly elevated thyroglobulin levels), without evidence of structural disease, comprises observation and surveillance with appropriate imaging studies performed at time intervals guided by the thyroglobulin doubling time.[83] 

Patients with suspected structural neck recurrence (biopsy-proven persistent or recurrent disease) may require additional therapies or may be managed with observation and serial cross-sectional imaging (e.g., contrast-enhanced computed tomography [CT] or magnetic resonance imaging [MRI]) at a frequency sufficient to identify clinically significant disease progression.[83] Recurrent structural disease that measures 8-10 mm or larger on anatomic imaging in the central and lateral neck, respectively, is considered for revision surgery.[1][83]

Metastases are observed most frequently in patients with aggressive histologic subtypes, and may occur in up to 10% of patients with differentiated thyroid cancer.[74][84]​ For the management of metastatic differentiated thyroid cancer, the American Thyroid Association recommends a preferred hierarchy of surgical excision of locoregional disease, radioactive iodine therapy for radioactive iodine-responsive disease (with TSH-suppressive therapy), directed local therapies (e.g., external beam radiation therapy, thermal ablation), and systemic therapy with kinase inhibitors.[1]

For patients with stable or slowly progressive asymptomatic metastatic disease, TSH-suppressive thyroid hormone therapy alone can be used.[1]

If distant metastases are radioactive iodine-responsive, radioactive iodine therapy is repeated every 6-12 months depending on rate of growth and response; however, uncertainty exists around the optimal activity and how it should be determined (empiric vs. dosimetric activities), as well as the potential long-term complications.[85] As tumors progress, they may lose their ability to concentrate radioactive iodine.[33] Radioactive iodine refractoriness occurs in around 60% to 70% of metastatic thyroid cancers, but less than 5% of all patients with thyroid cancer.[33]

Systemic therapy for recurrent or metastatic differentiated thyroid cancer

Treatment with kinase inhibitors, or other targeted therapies, may be considered for patients with progressive differentiated thyroid cancer who are not suitable for or not responsive to local treatment (including surgery and radioactive iodine therapy).

Genetic testing to identify potential actionable mutations/alterations (e.g., NTRK, BRAF, RET, mismatch repair deficiency [dMMR], microsatellite instability [MSI], tumor mutational burden [TMB]) is recommended prior to initiating therapy.[37][72]​​[46]​​​​

If systemic therapy is indicated, the following kinase inhibitors are recommended first-line options:[37] 

  • Lenvatinib

  • Sorafenib

Alternative kinase inhibitors that may be considered include:[37] 

  • Cabozantinib (if progression occurs after lenvatinib and/or sorafenib)

  • Larotrectinib or entrectinib or repotrectinib (for NTRK gene fusion-positive advanced solid tumors)

  • Selpercatinib or pralsetinib (for RET gene fusion-positive tumors).

Targeted therapies that may be considered for patients with unresectable recurrent or metastatic solid tumors that have progressed following prior treatment with no satisfactory alternative treatment options, include:[37] 

  • Pembrolizumab (a programmed death receptor-1 [PD-1]-blocking monoclonal antibody for patients with TMB-high [≥10 mutations/megabase] tumors, or MSI-high or dMMR tumors)

  • Dabrafenib plus trametinib (for patients with BRAF V600E mutation).

The optimal sequence of systemic therapy in this setting is unclear. Decision-making should be based on factors including expected treatment response, drug safety profile, and patient preference.

Anaplastic thyroid cancer

Anaplastic thyroid cancer is usually diagnosed at an advanced stage (often with distant metastases), displays extremely aggressive behavior, and is associated with a very poor prognosis.[13][74]

Early multidisciplinary involvement including the palliative care teams is important to support patient decision-making.[13] Determining the extent of disease and assessing for mutations influences the treatment options (including eligibility for clinical trials) and goals of care.[13]

Combining multiple therapeutic modalities (surgery, radiation therapy, systemic therapy [chemotherapy, targeted therapy]) is the most effective approach to treating anaplastic thyroid cancer, but needs to be individualized to optimally balance risks and benefits.[13][37]​ 

Radioactive iodine therapy is not used because anaplastic tumors do not take up radioiodine.[13][37]

Anaplastic thyroid cancer: management approaches

If possible, a total thyroidectomy is done. Determining whether a patient is a candidate for surgery depends on the tumor's resectability, extent of local invasion, need for urgent tracheostomy, presence of distant metastases, and the patient's performance status and treatment goals.[13]​ Thyroid hormone replacement is required post-total thyroidectomy.

Regardless of the surgical status, radiation therapy should be considered early in the treatment of anaplastic thyroid cancer.[86]

Chemotherapy with paclitaxel, docetaxel, or combined treatments (e.g. carboplatin/paclitaxel, docetaxel/doxorubicin) is associated with very low response rates and significant toxicities. Chemotherapy may, however, be considered:[13]

  • for its radiosensitizing effect when combined with radiation therapy, or

  • as a bridge to targeted therapy by patients awaiting results of molecular profiling.

Use of targeted therapy in patients with anaplastic thyroid cancer depends on the results of genetic testing.[13][37][46]​​[87][88]

  • Dabrafenib plus trametinib: may be considered prior to surgery (to improve resectability) in patients with the BRAF V600E mutation and locoregional disease.

  • Larotrectinib or entrectinib or repotrectinib: for patients with NTRK gene fusion-positive advanced solid tumors.

  • Selpercatinib or pralsetinib: for patients with RET gene fusion-positive tumors.

  • Immunotherapy: for example, pembrolizumab, for patients with TMB-H tumors.

Medullary thyroid cancer

Surgery for patients with sporadic or hereditary medullary thyroid cancer is total thyroidectomy and central compartment lymph node dissection, the extent of which depends on the serum calcitonin levels and ultrasound findings.[4][53]​​​[37][74]

Thyroid hormone replacement is required after total thyroidectomy to maintain serum TSH levels in the euthyroid range.[4] Medullary thyroid cancer is not TSH-sensitive; therefore, suppressive doses of TSH are not required. 

Medullary thyroid cancer: recurrence and metastatic disease

Recurrences are treated with additional surgery, plus external beam radiation therapy if local control cannot be achieved.[89] In metastatic disease, surgery may be indicated for patients in whom a single or a few metastases are located in the brain, lungs, or liver.[89] Focal treatments including external beam radiation therapy, stereotactic radiosurgery, radiofrequency ablation, or chemoembolization are used depending on the site of metastases.[4][89]

Kinase inhibitors have produced high response rates in patients with metastatic medullary thyroid cancer.[89] The multikinase inhibitors cabozantinib and vandetanib are recommended for first-line systemic therapy for patients with progressive, metastatic medullary thyroid cancer.[4][37][46][72]​​​ ​​​ The RET kinase inhibitors selpercatinib and pralsetinib are recommended for patients with recurrent or metastatic RET-mutated medullary thyroid cancer.[37][46]

Thyroid lymphoma

Management of primary thyroid lymphoma depends on the disease subtype and stage.[5]

See Non-Hodgkin lymphoma and MALT lymphoma topics for management of thyroid lymphoma.

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