Thyroid Cancer

Thyroid cancers represent approximately 1% of new cancer diagnoses in the United States each year. Thyroid malignancies are divided into papillary carcinomas (80%), follicular carcinomas (10%), medullary thyroid carcinomas (5-10%), anaplastic carcinomas (1-2%), primary thyroid lymphomas (rare), and primary thyroid sarcomas (rare).

Hürthle cell carcinoma is a rare thyroid malignancy that is often considered a variant of follicular carcinoma. Hürthle cell carcinomas account for 2-3% of all thyroid malignancies. They occur more commonly in women than in men and typically manifest in the fifth decade of life. The clinical presentation is similar to that of other thyroid malignancies. See the image below.

For summarized information on staging and treatment, see Thyroid Cancer Staging and Thyroid Cancer Treatment Protocols.

Signs and symptoms of thyroid cancer

Thyroid carcinoma most commonly manifests as a painless, palpable, solitary thyroid nodule. Patients or clinicians discover most of these nodules during routine palpation of the neck.

Signs and symptoms associated with malignancy in thyroid nodules include the following:

• Solitary nodules: Most likely to be malignant in patients older than 60 years and in patients younger than 30 years

• Increased rate of malignancy in males

• Nodular growth

• Rapid growth: Ominous sign

• Usually painless (nontender to palpation); sudden onset of pain more strongly associated with benign disease (eg, hemorrhage into a benign cyst, subacute viral thyroiditis)

• Hard and fixed nodules

Diagnosis of thyroid cancer

The key to the workup of the solitary thyroid nodule is to differentiate malignant from benign disease and, thus, to determine which patients require intervention and which patients may be monitored serially. History taking, physical examination, laboratory evaluation, and fine-needle aspiration biopsy (FNAB) are the mainstays in the evaluation of thyroid nodules. Imaging studies can be adjuncts in select cases.

Examination in patients suspected of thyroid cancer includes the following:

• Thorough head and neck examination, including thyroid gland and cervical soft tissues

• Indirect laryngoscopy

Firm cervical masses are highly suggestive of regional lymph node metastases. Vocal fold paralysis implies involvement of the recurrent laryngeal nerve.

Procedures

FNAB is the most important diagnostic tool in evaluating thyroid nodules and should be the first intervention. The following are the 4 possible results from this procedure:

• Benign disease

• Malignant disease

• Indeterminate for diagnosis

• Nondiagnostic

Up to 50% of repeated biopsies result in a definitive diagnosis. Patients whose findings are indeterminate or nondiagnostic despite repeat biopsy can undergo surgery for lobectomy for tissue diagnosis. Nondiagnostic cases can also be monitored clinically, and radioiodine scans can be useful for determining the functional status of the nodule, because most hyperfunctioning nodules are benign.

Laboratory testing

The following laboratory studies may be used to assess patients with suspected thyroid cancer:

• Serum thyroid-stimulating hormone concentration: Sensitive for hyperthyroidism/hypothyroidism and for evaluation of solitary thyroid nodules

• Serum calcitonin/pentagastrin-stimulated calcitonin levels: Elevated levels highly suggestive of medullary thyroid carcinoma

• Polymerase chain reaction (PCR) assay for germline mutations in the RET proto-oncogene: For diagnosis of familial medullary thyroid carcinoma

Imaging studies

The following imaging studies may be used to evaluate patients with suspected thyroid cancer:

• Neck ultrasonography: Most common modality to evaluate thyroid disease; however, limited usefulness for distinguishing between malignant and benign nodules

• Thyroid radioiodine imaging: To determine functional status of a nodule but cannot exclude carcinoma

• Neck computed tomography (CT) scanning or magnetic resonance imaging (avoid iodinated contrast agents): To evaluate soft-tissue extension of large or suspicious thyroid masses into the neck, trachea, or esophagus, and to assess metastases to the cervical lymph nodes; no role in routine management of solitary thyroid nodules

A 2015 consensus statement from the American Thyroid Association on preoperative imaging for thyroid cancer surgery stated the following ^{[1, 2]} :

• Ultrasonography remains the most important imaging modality in the evaluation of thyroid cancer and should be used routinely to assess the primary tumor and all associated cervical lymph node basins preoperatively

• Ultrasonographically guided fine-needle aspiration of suspicious lymph nodes may be useful in guiding the extent of surgery

• Cross-sectional imaging (CT scanning with contrast or magnetic resonance imaging [MRI]) may be considered in select circumstances to better characterize tumor invasion and bulky, inferiorly located, or posteriorly located lymph nodes; it may also be used when ultrasonographic expertise is not available

Management of thyroid cancer

Malignant diagnoses require surgical intervention. Papillary thyroid carcinoma and medullary thyroid carcinoma are often positively identified on the basis of FNAB results alone. Cervical metastases discovered preoperatively or intraoperatively should be removed by means of en bloc lymphatic dissection of the respective cervical compartment (selective neck dissection) while sparing the nonlymphatic structures.

Well-differentiated neoplasms

Patients with follicular neoplasm, as determined with FNAB results, should undergo surgery for thyroid lobectomy for tissue diagnosis. The extent of surgical therapy for well-differentiated neoplasms is controversial. Primary treatment for papillary and follicular carcinoma is surgical excision whenever possible. Total thyroidectomy has been the mainstay for treating well-differentiated thyroid carcinoma. Modifications to total thyroidectomy include subtotal thyroidectomy to reduce the risk of recurrent laryngeal nerve injury and hypoparathyroidism.

A 2015 consensus statement from the American Thyroid Association on the management of patients with differentiated thyroid cancer who have recurrent/persistent nodal disease stated the following ^{[1, 3]} :

• The appropriate management of patients with nodal metastases may involve compartmental lymph-node dissection, active surveillance, radioactive iodine ablation therapy, external-beam radiation therapy, and/or nonsurgical, image-guided, minimally invasive ablative approaches

• Biologic considerations include aggressive histology, extrathyroidal extension of primary tumor, and molecular prognosis for aggressive biology

• Surgical/technical considerations include prior recurrences in the same or different compartments

Hürthle cell carcinomas

For patients with Hürthle cell carcinomas based on initial FNAB findings, most surgeons advocate an aggressive approach with lobectomy and isthmectomy, followed by completion thyroidectomy with confirmation on final pathologic result. For tumors larger than 5 cm or for palpable lymphatic metastases, total thyroidectomy (including neck dissection for palpable lymph nodes) is often performed during the initial operation.

Medullary thyroid carcinomas and familialmedullary thyroid carcinomas

Sporadic medullary thyroid carcinomas and familial medullary thyroid carcinomas are treated with total thyroidectomy and lymphatic dissection of the anterior compartment of the neck. If the vasculature of the parathyroid gland is disrupted, autotransplantation of the parathyroid gland into the sternocleidomastoid muscle or the nondominant forearm is performed. In children with multiple endocrine neoplasia (MEN) type 2A and MEN 2B syndromes, prophylactic thyroidectomy and central-compartment lymph-node dissection is performed.

Anaplastic thyroid carcinoma, primary thyroid lymphoma, thyroid sarcoma

Total or subtotal thyroidectomy is performed for anaplastic thyroid carcinoma when the extent of the tumor permits it. Tracheotomy is needed in cases with airway compromise due to tracheal invasion.

Stage IE lymphomas may be treated with total thyroidectomy followed by postoperative radiation therapy. Surgical excision should not be performed if local infiltration into surrounding tissues is evident. Stage IIE lymphomas are treated with combined chemotherapy and radiation therapy. Doxorubicin or CHOP (ie, cyclophosphamide, hydroxydaunomycin, Oncovin [vincristine], prednisone) is the commonly used chemotherapeutic regimen.

The treatment for thyroid sarcomas is total thyroidectomy. Radiation therapy may be used in an adjunctive setting.

Postsurgical management

After total thyroidectomy, patients undergo radioiodine scanning to detect regional or distant metastatic disease, followed by radioablation of any residual disease found. In addition, patients are given thyroid replacement therapy with T4 or triiodothyronine (T3).

In patients with anaplastic thyroid carcinoma, chemotherapy and radiation therapy are typically administered in combination. Postoperative external-beam irradiation is effective in improving local control; this may also be used as primary treatment in unresectable cases. Chemotherapy (most commonly doxorubicin) is added for palliation.

Thyroid malignancy occurs with relative infrequency in the United States, although benign thyroid disease is relatively common. Although patients with thyroid cancers generally have a favorable prognosis compared with that of patients with many other solid tumors, the American Cancer Society (ACS) estimated that about 2200 deaths from thyroid cancer would occur in the United States in 2021. ^[4] Contemporary treatment of patients with thyroid malignancy requires a multidisciplinary approach involving an endocrinologist, a thyroid surgeon, a radiologist, and, on occasion, medical and radiation oncologists.

In a European study of 86,690 patients with thyroid cancer, Dal Maso et al found that between 2000 and 2007, the 5-year relative thyroid cancer survival rates in men and women were 81% and 88%, respectively. Between 1999 and 2007, the 5-year relative survival rate for all thyroid cancers rose by 5%, although for papillary and follicular cancers, specifically, the increase was only 2% and 4%, respectively. ^[5]

For patient education information, see the Thyroid and Metabolism Center, as well as the patient education article Thyroid Problems.

An image of Hurthle cells can be seen below.

Frequency

Thyroid cancers represent approximately 1% of new cancer diagnoses each year. The ACS estimated that 44,280 new cases of thyroid cancer would be diagnosed in 2021; ^[4]  papillary thyroid carcinoma accounts for about 80% of all thyroid carcinomas in the United States. The incidence of the thyroid cancer is three times higher in women than in men ^[4] and peaks in the third and fourth decades of life.

The US incidence of thyroid cancer has more than tripled since the late 20th century, growing from nearly 5.0 new cases per 100,000 persons in 1975 to 15.5 new cases per 100,000 persons per year in the period between 2014 and 2018. ^{[6, 7]} Much of the increase has been due to a rise in the incidence of papillary thyroid cancer, which grew from 7.8 cases per 100,000 persons in 2003 to 15.4 cases per 100,000 persons in 2013. ^[7]

Thyroid cancers are divided into papillary carcinomas, follicular carcinomas, medullary thyroid carcinomas (MTCs), anaplastic carcinomas, primary thyroid lymphomas, and primary thyroid sarcomas. Papillary carcinoma represents 80% of all thyroid neoplasms. Follicular carcinoma is the second most common thyroid cancer, accounting for approximately 10% of cases. MTCs represent 5-10% of neoplasms. Anaplastic carcinomas account for 1-2%. Primary lymphomas and sarcomas are rare.

Using data on 497 US counties from the SEER Program, Morris et al found that the tripling of the incidence of papillary thyroid cancer in the past 3 decades is directly correlated with demographic and age-based markers of access to health care, suggesting widespread overdiagnosis of the disease. Supporting this conclusion, rates of mortality from thyroid cancer remained stable during this period (staying at about 0.5 deaths per 100,000 individuals between 1975 and 2009, according to the aforemention study by Davies and colleagues). ^{[8, 9, 10]}

Etiology

Thyroid carcinomas arise from the 2 cell types present in the thyroid gland. The endodermally derived follicular cell gives rise to papillary, follicular, and probably anaplastic carcinomas. The neuroendocrine-derived calcitonin-producing C cell gives rise to MTCs. Thyroid lymphomas arise from intrathyroid lymphoid tissue, whereas sarcomas likely arise from connective tissue in the thyroid gland.

Radiation exposure significantly increases the risk for thyroid malignancies, particularly papillary thyroid carcinoma. This finding was observed in children exposed to radiation after the nuclear bombings in Hiroshima and Nagasaki during World War II. Additional evidence was gathered after atomic bombs were tested in the Marshall Islands, after the accident at the Chernobyl nuclear power plant, and in patients who received low-dose radiation therapy for benign disorders (eg, acne, adenotonsillar hypertrophy). Low-dose radiation exposure from imaging studies has not been found to have a tumorigenic effect. Radiation targeting the thyroid gland (eg, iodine-131 ablation of the thyroid) or high-dose external-beam radiation therapy does not appear to increase the risk of papillary thyroid carcinoma. This is presumably because cell killing increases with these doses.

A study by Le et al indicated that among patients in the Veterans Health Administration (VHA) with thyroid cancer, the percentage of those with self-reported exposure to Agent Orange is significantly higher than in the general VHA population. The study included 19,592 patients diagnosed with thyroid cancer. ^[11]

Low dietary intake of iodine does not increase the incidence of thyroid cancers overall. However, populations with low dietary iodine intake have a high proportion of follicular and anaplastic carcinomas.

History

Thyroid carcinoma most commonly manifests as a painless, palpable, solitary thyroid nodule. Patients or physicians discover most of these nodules during routine palpation of the neck. Palpable thyroid nodules are present in approximately 4-7% of the general population, and most represent benign disease. High-resolution ultrasonography reportedly depicts thyroid nodules in 19-67% of randomly selected individuals. An estimated 5-10% of solitary thyroid nodules are malignant. Palpable and nonpalpable nodules of similar size have the same risk of malignancy.

The patient's age at presentation is important because solitary nodules are most likely to be malignant in patients older than 60 years and in patients younger than 30 years. In addition, thyroid nodules are associated with an increased rate of malignancy in male individuals. Growth of a nodule may suggest malignancy. Rapid growth is an ominous sign.

Malignant thyroid nodules are usually painless. Sudden onset of pain is more strongly associated with benign disease, such as hemorrhage into a benign cyst or subacute viral thyroiditis, than with malignancy.

Hoarseness suggests involvement of the recurrent laryngeal nerve and vocal fold paralysis. Dysphagia may be a sign of impingement of the digestive tract. Heat intolerance and palpitations suggest autonomously functioning nodules.

Medullary carcinoma can occur as part of multiple endocrine neoplasia (MEN) 2A or 2B syndrome, as well as familial MTC (FMTC) syndrome. Patients with a family history of thyroid cancer should be evaluated with vigilance.

Physical examination

Physical examination should include thorough head and neck examination with careful attention to the thyroid gland and cervical soft tissues, as well as indirect laryngoscopy.

Solitary thyroid nodules can vary from soft to hard. Hard and fixed nodules are more suggestive of malignancy than supple mobile nodules are. Thyroid carcinoma is usually nontender to palpation. Firm cervical masses are highly suggestive of regional lymph node metastases. Vocal fold paralysis implies involvement of the recurrent laryngeal nerve.

The key to the workup of the solitary thyroid nodule is to differentiate malignant from benign disease and, thus, to determine which patients require intervention and which patients may be monitored serially. History taking, physical examination, laboratory evaluation, and fine-needle aspiration biopsy (FNAB) are the mainstays in the evaluation of thyroid nodules. Imaging studies can be adjuncts in select cases.

A 2015 consensus statement from the American Thyroid Association on preoperative imaging for thyroid cancer surgery stated the following ^{[1, 2]} :

• Ultrasonography remains the most important imaging modality in the evaluation of thyroid cancer and should be used routinely to assess the primary tumor and all associated cervical lymph node basins preoperatively; positive lymph nodes may be distinguished from normal nodes based on size, shape, echogenicity, hypervascularity, loss of hilar architecture, and the presence of calcifications

• Ultrasonographically guided fine-needle aspiration of suspicious lymph nodes may be useful in guiding the extent of surgery

• Cross-sectional imaging (CT scanning with contrast or magnetic resonance imaging [MRI]) may be considered in select circumstances to better characterize tumor invasion and bulky, inferiorly located, or posteriorly located lymph nodes; it may also be used when ultrasonographic expertise is not available

• The above recommendations are applicable to initial and revision surgery; functional imaging with positron emission tomography (PET) or PET-CT scanning may be helpful in cases of recurrent cancer with positive tumor markers and negative anatomic imaging

Fine-needle aspiration biopsy

FNAB is the most important diagnostic tool in evaluating thyroid nodules and should be the first intervention. The technique is inexpensive and easy to perform, and it causes few complications.

To perform FNAB, comfortably position both the patient and the physician. Extend the patient's neck slightly and palpate the nodule with the nondominant hand. Clean the skin with alcohol and infiltrate the area with local anesthesia. Place a 21- to 25-gauge needle on the end of a syringe. Many physicians use trigger-style aspirating handles on the syringe. Introduce 2 mL of air into the syringe, and place the needle into the skin. Apply negative pressure to the syringe, and pass the needle through the nodule, which is identified by using the nondominant hand. After several passes, release the negative pressure, and withdraw the needle. Use the air remaining in the syringe to expel the specimen from the hub and needle onto a glass slide or into cytologic solution for a cell block. Fix the slide in alcohol for Papanicolaou and hematoxylin-eosin staining. Some slides can be air dried and stained with Romanowsky stain (Diff-Quick).

Successful diagnosis by the cytologist depends on accurate sampling of the nodule and specimen cellularity. For this reason, several authors recommend performing at least 3 aspirations to ensure adequacy of the specimen and to minimize false-negative results. Ultrasonographic guidance can help to increase the accuracy of FNAB. Danese et al report increased false-negative rates with palpation FNAB compared with ultrasonography-guided FNAB.

The 4 results from FNAB are benign disease, malignant disease, indeterminate for diagnosis, and nondiagnostic. In their review of several large series, Gharib and Goellner (1993) found that 69% of FNAB results were benign, 4% were malignant, 10% were indeterminate, and 17% were nondiagnostic. ^[12] Their false-positive rate was 2.9%, and their false-negative rate was 5.2%. Sensitivity and specificity were 83% and 92%, respectively.

Results of FNAB determine the next step in managing the thyroid nodule. A definitive diagnosis is obtained in as many as 50% of repeated biopsies. Patients whose findings are nondiagnostic despite repeat biopsy can undergo surgery for lobectomy for tissue diagnosis, or they can be monitored clinically. In these circumstances, radioiodine scans can be useful for determining the functional status of the nodule, as most hyperfunctioning nodules are benign.

Indeterminate biopsy findings are labeled suspicious at some institutions. When cellular material is adequate for evaluation but when malignant and benign disease cannot be differentiated, biopsy results can be labeled suspicious. Patients with a suspicious diagnosis should undergo lobectomy for definitive diagnosis.

Malignant diagnoses require surgical intervention. Papillary thyroid carcinoma and MTC are often positively identified on the basis of FNAB results alone. In patients with these carcinomas, definitive surgical planning can be undertaken at the outset. However, it is nearly impossible to distinguish a follicular adenoma from a follicular carcinoma on the basis of FNAB findings. Patients with follicular neoplasm, as determined with FNAB results, should undergo surgery for thyroid lobectomy for tissue diagnosis. These patients require complete thyroidectomy if a malignancy is discovered on review of the pathology. Some controversy exists regarding the extent of thyroidectomy (total thyroidectomy, subtotal thyroidectomy, or lobectomy) for a particular pathologic diagnosis. Each pathologic diagnosis and its corresponding extent of thyroidectomy are discussed below.

Complications of FNAB are few and generally minor. The most common complications are minor hematoma, ecchymosis, and local discomfort. Clinically significant hematoma and swelling is exceedingly rare. Inadvertent puncture of the trachea, carotid artery, or jugular vein usually does not cause clinically significant problems and is managed with the application of local pressure.

Laboratory evaluation

The serum thyroid-stimulating hormone (TSH) concentration is a highly sensitive measure for hyperthyroidism or hypothyroidism. A sensitive TSH assay is useful in the evaluation of solitary thyroid nodules. A low serum TSH value suggests an autonomously functioning nodule, which typically is benign. However, malignant disease cannot be ruled out on the basis of low or high TSH levels.

Other thyroid function tests are usually not necessary in the initial workup. Serum thyroglobulin measurements are not helpful diagnostically because they are elevated in most benign thyroid conditions.

Elevated serum calcitonin levels are highly suggestive of MTC. Serum calcitonin measurement, which was once the mainstay in the diagnosis of FMTC, has been replaced by sensitive polymerase chain reaction (PCR) assays for germline mutations in the RET proto-oncogene. These mutations are present in patients with MEN 2A, MEN 2B, and FMTC (see Genetic testing for MEN and FMTC in the Medullary Thyroid Carcinoma section). However, calcitonin and the more sensitive pentagastrin-stimulated calcitonin are used as tumor markers to monitor patients who have been treated for MTC. Because of the low incidence of MTC overall, testing of serum calcitonin is not a cost-effective screening tool in the primary workup of thyroid nodules.

Imaging procedures

Ultrasonography is the imaging modality most commonly used to evaluate thyroid disease. This noninvasive study enables accurate evaluation of the thyroid gland. However, the usefulness of ultrasonography for distinguishing between malignant and benign nodules is limited. Simple cysts found on sonograms are benign, but simple cysts are rarely found. Cysts are most commonly complex, with at least some solid component that could potentially harbor malignancy. Microcalcifications noted on sonograms are associated with thyroid malignancy. Ultrasonography is highly sensitive for thyroid nodules and can depict nodules only a few millimeters in size.

A sonogram ordered to evaluate a solitary nodule often reveals additional nodules of questionable clinical significance. The accuracy of FNAB results increases when sonographic guidance is used. Use of ultrasonography-guided FNAB can be useful for biopsy of small or difficult-to-palpate thyroid nodules as well as for FNAB of nodules in children. Ultrasonography can also be useful for accurate measurement of thyroid nodules that are being monitored serially.

In 2013, researchers at the Mayo Clinic reported that recent dramatic increases in the diagnosis of low-risk thyroid cancer in the United States are fuelled by the overuse of ultrasonography. ^{[13, 14]} The incidence of thyroid cancer in the United States has tripled in the past 3 decades, from 3.6 per 100,000 in 1973 to 11.6 per 100,000 in 2009, making it one of the fastest growing diagnoses. The vast majority of the thyroid tumors being detected are small low-risk papillary thyroid cancers that are unlikely to ever progress enough to cause symptoms or death. That this represents overdiagnosis is supported by the observation that the death rate for these cancers has remained stable (0.5 per 100,000 in 1979 and in 2009), even with the increasing incidence. ^{[13, 14]}

Radioiodine imaging can help in determining the functional status of a nodule. Nonfunctional nodules do not take up radiolabeled iodine-123 and appear as cold spots in the thyroid (cold nodules). ^[15] Hyperfunctioning nodules take up radioiodine and appear as hot spots (hot nodules). Warm nodules appear similar to the surrounding normal thyroid tissue. Hot or warm nodules were historically thought to be benign; therefore, they did not require further evaluation for malignancy. However, in a review of 5000 patients undergoing thyroidectomy regardless of radioimaging findings, Ashcraft and Van Herle (1981) found that 4% of hot nodules harbored malignancy.

Carcinoma cannot be excluded on the basis of radioiodine scans. Therefore, radioiodine scans are usually not helpful for the routine evaluation of thyroid nodules. In select situations, radioiodine studies can be diagnostic adjuncts. When results of repeated FNAB of a nodule are nondiagnostic, a radioiodine imaging can help in directing management if a hot nodule is to be monitored clinically.

CT scanning and MRI can be used to evaluate soft-tissue extension of large or suspicious thyroid masses into the neck, trachea, or esophagus and to assess metastases to the cervical lymph nodes. These studies do not have a role in the routine management of solitary thyroid nodules. The use of iodinated contrast agents should be avoided in patients with possible thyroid carcinoma because they interfere with the postoperative use of radioactive iodine.

A 2015 consensus statement from the American Thyroid Association on the management of patients with differentiated thyroid cancer who have recurrent/persistent nodal disease stated the following ^{[1, 3]} :

• The appropriate management of patients with nodal metastases may involve compartmental lymph-node dissection, active surveillance (watchful waiting with serial cervical ultrasonographic evaluations), radioactive iodine ablation therapy, external-beam radiation therapy, and/or nonsurgical, image-guided, minimally invasive ablative approaches

• Biologic considerations include aggressive histology, extrathyroidal extension of primary tumor, and molecular prognosis for aggressive biology

• Surgical/technical considerations include prior recurrences in the same or different compartments

A study by Weber et al indicated that in patients with differentiated thyroid cancer, the presence of minimal extrathyroidal extension (M-ETE) does not correlate with a greater risk for metastases at initial diagnosis. The investigators reported that the prevalence of N1/M1 disease in study patients with M-ETE was comparable to that in patients with no extension, at initial diagnosis (42.5% vs 32.5%, respectively). It was also found that the recurrence rate did not differ between the two groups, although this result may have been influenced by the fact that treatment tended to be intensified in individuals with M-ETE. Follow-up time in the study was at least 5 years. ^[16]

Papillary carcinoma

Clinical features

Papillary carcinoma is the most common thyroid malignancy, representing approximately 80%. Papillary carcinoma and follicular carcinoma make up the well-differentiated thyroid carcinomas. Women develop papillary cancer 3 times more frequently than men do, and the mean age at presentation is 34-40 years.

Cases can occur familially, either alone or in association with Gardner syndrome (familial adenomatous polyposis). As noted above, radiation exposure, especially during childhood, is associated with the development of papillary thyroid carcinoma. Tumors typically appear after a latency period of about 10-20 years. In addition, an increased incidence of papillary cancer is hypothesized among patients with Hashimoto thyroiditis (chronic lymphocytic thyroiditis). Despite this possibility, the rate of malignancy for a given nodule in people with Hashimoto thyroiditis is similar to that of individuals with a normal gland.

Papillary carcinoma is a slow-growing tumor that arises from the thyroxine (T4)- and thyroglobulin-producing follicular cells of the thyroid. The cells are TSH sensitive and take up iodine. They produce thyroglobulin in response to TSH stimulation. This feature has both diagnostic and therapeutic value for managing residual disease and recurrences after surgical excision (see Treatment and Prognosis below).

Pathology

On gross pathologic examination, papillary carcinomas are whitish invasive neoplasms with ill-defined margins. Under microscopy, the tumors are unencapsulated neoplasms that characteristically grow with papillae consisting of neoplastic epithelium overlying fibrovascular stalks. Very differentiated tumors can have a complex arborizing pattern. Nuclei have an empty ground-glass appearance with characteristic nuclear grooves and pseudoinclusions. Mitoses are rare.

Another histologic feature is the presence of psammoma bodies, which occur in 50% of papillary carcinomas. Psammoma bodies are calcific concretions that have a circular laminated appearance. They are found in the stroma of the tumor. In addition, many papillary carcinomas contain areas that show a follicular growth pattern. However, when the nuclear features in follicular areas are the same as those in papillary areas, the tumor behaves like a classic papillary carcinoma and should be designated as such. Papillary carcinoma may be multicentric, with foci present in both the ipsilateral and contralateral lobes.

Local invasion

Tumors can grow directly through the thyroid capsule to invade surrounding structures. Growth into the trachea can occur, producing hemoptysis. Extensive involvement can cause airway obstruction. The recurrent laryngeal nerves can become involved because of their proximity in the tracheoesophageal groove. Patients present with a hoarse, breathy voice and, occasionally, dysphagia.

Regional and metastatic disease

Another common feature of papillary carcinoma is its propensity to spread to the cervical lymph nodes. Clinically evident lymph node metastases are present in approximately one third of patients at presentation. Microscopic metastases are present in one half. The most common site of lymph node involvement is in the central compartment (level 6) located medial to the carotid sheaths on both sides, with extension from the hyoid bone superiorly to the sternal notch inferiorly. The jugular lymph node chains (levels 2-4) are the next most common sites of cervical node involvement. Lymph nodes in the posterior triangle of the neck (level 5) may also develop metastases. This finding has important implications on the treatment algorithm for patients in this situation (see Treatment and Prognosis below and the images below).

A study by Kim et al indicated that in patients with papillary thyroid cancer, a tumor size of greater than 1 cm and nonretroesophageal lateral lymph node metastasis are independent predictors of right retroesophageal lymph node metastasis. ^[17]

Approximately 5-10% of patients with papillary thyroid carcinoma develop distant metastases. Distant spread of papillary carcinoma typically affects the lungs and bone.

Follicular carcinoma

Clinical features

Follicular carcinoma is the second most common thyroid malignancy and represents about 10% of thyroid cancers. Follicular carcinoma represents an increased portion of thyroid cancers in regions where dietary intake of iodine is low. Similar to papillary carcinoma, follicular carcinoma occurs 3 times more frequently in women than in men. Patients with follicular carcinoma are typically older than those with papillary carcinoma at presents. The mean age range at diagnosis is late in the fourth to sixth decades.

Like papillary carcinomas, follicular carcinomas arise from the follicular cells of the thyroid. The neoplastic cells are TSH sensitive as well, taking up iodine and producing thyroglobulin—a feature that is exploited diagnostically and therapeutically (see Postoperative radioiodine scanning and ablation below).

Pathology

On gross pathology, the tumors appear as round, encapsulated, light brown neoplasms. Fibrosis, hemorrhage, and cystic changes are found in the lesions. Under microscopy, the tumors contain neoplastic follicular cells, which overall can have a solid, trabecular, or follicular growth pattern (that usually produces microfollicles). The follicular cells in these tumors do not have characteristic features like papillary carcinoma cells.

Follicular carcinomas are differentiated from benign follicular adenomas by tumor capsule invasion and/or vascular invasion. For this reason, differentiating follicular adenomas from follicular carcinomas is extremely difficult with FNAB cytology and frozen section analysis. The tumors are divided into minimally invasive and widely invasive lesions depending on the histologic evidence of capsule and vascular invasion. Immunohistochemical staining for thyroglobulin and cytokeratins is nearly always positive.

Local invasion

Local invasion can occur as it does with papillary carcinoma, with the same presenting features (see Local invasion for Papillary Carcinoma, above).

Cervical and distant metastases

Unlike papillary carcinoma, cervical metastases from follicular carcinomas are uncommon. However, the rate of distant metastasis is significantly increased (approximately 20%). Lung and bone are the most common sites.

Surgical treatment

The extent of surgical therapy for well-differentiated neoplasms is controversial. Primary treatment for papillary and follicular carcinoma is surgical excision whenever possible. Total thyroidectomy has been the mainstay for treating well-differentiated thyroid carcinoma. In this procedure, all apparent thyroid tissue is surgically removed. Major complications in this procedure are recurrent laryngeal nerve injury and hypoparathyroidism from inadvertent damage or removal of the parathyroid glands. Complications associated with total thyroidectomy are discussed in the Technique of Thyroidectomy section below.

After total thyroidectomy, patients undergo radioiodine scanning to detect regional or distant metastatic disease (see Postoperative radioiodine scanning and ablation below), followed by radioablation of any residual disease found.

Over the years, modifications to total thyroidectomy have been proposed in an effort to reduce recurrent laryngeal nerve injury and hypoparathyroidism associated with total thyroidectomy. Subtotal thyroidectomy has been proffered as an alternative to total thyroidectomy. With subtotal thyroidectomy, a small portion of gross thyroid tissue opposite the side of malignancy is left in place to minimize the risk of injuring the recurrent laryngeal nerve and of inadvertently removing the parathyroid glands on that side. Patients usually receive postoperative radioiodine treatment in an attempt to ablate the remaining thyroid tissue.

With improved stratification of patients into prognostic groups (see Prognostic factors below), some surgeons have proposed thyroid lobectomy with isthmectomy alone as definitive treatment for patients at low risk for recurrent or metastatic disease. This approach remains to be substantiated as a feasible alternative to total thyroidectomy.

Using the Surveillance, Epidemiology, and End Results (SEER) database, one study compared the overall survival (OS) and cause-specific survival (CSS) of 23,605 subjects with papillary or follicular thyroid cancer treated with local excision, lobectomy, near-total thyroidectomy, or total thyroidectomy. The 10-year OS and CSS results concluded that total thyroidectomy resulted in improved survival over other techniques; poorer outcomes were associated with age, stage T3/T4 disease, positive nodes, and tumor size. ^[18]

According to a 2009 study by Asari et al, of 207 patients with follicular thyroid carcinoma, the 127 patients with minimum growth had no lymph node metastases. The authors state that thyroidectomy is still recommended for all patients with follicular thyroid carcinoma, although patients with widely invasive disease may need more aggressive surgical treatment. Patients with minimal disease invasion have an excellent prognosis with limited need for nodal surgery. ^[19]

Management of neck

The neck must be thoroughly examined for lymphatic metastases. Ultrasonography of the neck with particular attention to the central compartment (level 6) is an effective diagnostic approach. FNAB of suspicious lymph nodes can be performed. Cervical metastases discovered preoperatively or intraoperatively should be removed by means of en bloc lymphatic dissection of the respective cervical compartment (selective neck dissection) while sparing the nonlymphatic structures. Excision of single nodes, known as berry picking, is inadequate therapy for metastatic disease. Elective neck dissection (removal of clinically benign neck lymphatic tissue) in a well-differentiated carcinoma is not indicated because postoperative radioiodine treatment effectively treats microscopic lymphatic metastases.

Postoperative radioiodine scanning and ablation

Because differentiated thyroid tissue and well-differentiated thyroid carcinomas are TSH sensitive and because they take up iodine, radioiodine preferentially targets residual normal or malignant tissue after thyroidectomy. Therefore, radioiodine can be given in diagnostic doses to detect residual normal or neoplastic tissue in the body and in therapeutic doses to ablate this tissue. After thyroidectomy, use of radioiodine scanning and ablation has become commonplace for diagnosing and treating residual thyroid tissue, as well as regional and distant metastases from well-differentiated thyroid carcinomas. Pretherapeutic iodine-uptake scanning is controversial because of its cost and because of concerns about¹³¹ I-induced tumor stunning, which may decrease the effectiveness of radioiodine treatment.

After thyroidectomy, patients are given thyroid replacement therapy with T4 (Synthroid) or triiodothyronine (T3, Cytomel).¹³¹ I or¹²³ I scanning is performed when the patient is in a hypothyroid state (TSH >30-50). Approximately 4-6 weeks after thyroidectomy, hypothyroid can be induced by discontinuing replacement (T4 for 4 weeks or T3 for 2 weeks) to obtain high serum TSH levels. A diagnostic dose of¹³¹ I or¹²³ I is given initially. Whole-body scanning is performed to detect any tissue taking up radioiodine. If any normal thyroid remnant or metastatic disease is detected, a therapeutic dose of¹³¹ I is administered to ablate the tissue. Posttreatment scanning should also be performed because it may reveal metastatic disease not otherwise noted.

The role of recombinant human TSH (Thyrogen) in remnant ablation continues to evolve. Thyrogen is approved for postsurgical remnant ablation in Europe but not the United States. Barbaro et al found equivalent results in postsurgical remnant ablation when they compared traditional T4 withdrawal with the discontinuation of T4 1 day before TSH stimulation. Thyrogen stimulation avoids the discomfort of patients having to discontinue thyroid replacement and is especially useful in those unable to tolerate hypothyroidism or to generate a high TSH level.

If a treatment dose of¹³¹ I is required, diagnostic thyroid scanning is repeated while the patient is in the hypothyroid state about 6 months after initial treatment. Again, if the diagnostic scan is positive, an additional therapeutic dose is given. This process is repeated until the diagnostic scan is negative.

A promising new development for follow-up thyroid scanning is the use of recombinant human TSH as opposed to withdrawing T4 to increase autogenous TSH levels. This approach avoids the discomfort of having to discontinue thyroid replacement therapy for these scans.

A retrospective analysis of more than 1000 patients with papillary thyroid cancer who underwent total thyroidectomies found that most patients with low-risk local disease and some with high-risk T3 tumors who did not receive radioiodine remnant ablation after surgery had high 5-year recurrence-free survival rates. This suggests that physicians should carefully consider whether the benefits outweigh the risks associated with radioiodine remnant ablation when debating the possibility of employing this technique in individual patients. ^{[20, 21]}

A study by Ruel et al indicated that adjuvant radioiodine therapy can improve the overall survival rate in patients with intermediate-risk papillary thyroid cancer. The study, which had a mean 6-year follow-up period, involved 21,870 adult patients who underwent total thyroidectomy for intermediate-risk papillary thyroid cancer, including 15,418 who received adjuvant radioiodine treatment and 6452 who did not. The investigators found that the risk of death was reduced by 29% in the radioiodine patients, with the risk decreased by 36% in those under age 45 years. ^[22]

Thyroid suppression

After thyroidectomy and radioiodine ablation, patients with well-differentiated thyroid carcinoma are maintained on thyroid-suppression suppression. Patients take T4 in daily doses sufficient to suppress TSH production by the pituitary. Low TSH levels in the bloodstream reduce tumoral growth rates and reduce recurrence rates of well-differentiated thyroid carcinomas. The extent to which TSH should be suppressed is controversial. Most authors recommend reducing TSH levels to 0.1 mU/L. This level provides adequate thyroid suppression while avoiding deleterious cardiac and bone effects of profound thyroid suppression.

Follow-up care

Patients are regularly monitored every 6-12 months with serial radioiodine scanning and serum thyroglobulin measurements after surgery and radioiodine therapy. Thyroglobulin is a useful marker of tumor recurrence because well-differentiated thyroid cancers synthesize thyroglobulin. However, it is useful only after total thyroid ablation. Serum thyroglobulin is measured at the time of follow-up thyroid scanning, during the withdrawal of thyroid hormone or the administration of recombinant TSH. Serum antithyroglobulin antibodies are measured in addition to thyroglobulin because their presence invalidates the assay. Thyroglobulin antibody levels should be obtained with each thyroglobulin measurement. Rising thyroglobulin level after thyroid ablation suggests recurrence. Ultrasonography of the neck can also be used to detect regional recurrences.

Pharmacologic therapy

Sorafenib (Nexavar) was approved in November 2013 for differentiated thyroid cancer (DTC) that is refractory to radioactive iodine treatment. In a study of 417 patients with progressive radioiodine-refractory DTC, treatment with sorafenib, an orally active inhibitor of VEGFR1-3 and Raf kinases, significantly improved progression-free survival (10.8 months) compared with placebo (5.8 months). ^{[23, 24, 25]} Tumor histology was 57% papillary, 25% follicular, and 10% poorly differentiated. The majority of the patients (96%) had metastatic disease, of which 71% of the target lesions were in the lung, 40% in lymph nodes, and 14% in bone.

At the time of the report, median overall survival had not yet been reached in either study arm, and 70% of placebo patients had started open-label sorafenib. ^{[23, 24]} Thus, all reported responses were partial: 12.2% in the sorafenib group vs 0.5% in the placebo group. The rate of stable disease for 6 months or longer was 42% in the sorafenib group and 33% in the placebo group.

A second oral VEGF inhibitor for refractory DTC was approved, in February 2015. Approval for lenvatinib (Lenvima) was based on the SELECT phase-3 trial. Compared with patients on placebo, those taking lenvatinib showed significant improvements in progression-free survival (median period of 18.3 months, compared with 3.6 months with placebo). The response rate among patients with iodine-131-refractory thyroid cancer was also significantly better with lenvatinib than with placebo. ^{[26, 27]}

Management of recurrence

Recurrences are best treated with surgical excision if the disease is clinically evident and surgically accessible. Nonlocalized recurrences detected on the basis of elevated thyroglobulin levels are treated with¹³¹ I. On occasion, recurrent tumors do not concentrate iodine. Positron emission tomography (PET) may be helpful in localizing disease in such circumstances. When surgical excision of recurrent disease is not feasible, external-beam radiation therapy may be useful. Chemotherapy, usually with doxorubicin, is reserved for tumors that do no respond to other treatments and for palliative care. Response rates of 35-40% are reported, though complete responses to chemotherapy are rare.

Prognostic factors

The long-term disease-free survival with aggressive treatment and management is nearly 90% overall. A variety of factors, as follow, are associated with prognosis:

• Age: The patient's age at diagnosis is one of the most important prognostic features of well-differentiated thyroid carcinoma; cancer-related death is most likely to occur if the patient is >40 years at the time of diagnosis; recurrences are most common in patients whose disease is diagnosed when they were < 20 years or >60 years

• Sex: Men are twice as likely as women to die from thyroid cancer

• Size: The size of the primary tumor is related to survival; patients with primary tumors >4 cm have increased recurrence and cancer-related mortality rates (although a study by Nguyen et al indicated that no association exists between increasing tumor size and survival in patients with thyroid cancer until the tumor reaches dimensions of >2.5 cm ^[28] )

• Histology: Overall, papillary carcinoma is associated a 30-year cancer-related death rate of 6%; follicular carcinoma has a 30-year cancer-related death rate of 15%

• Local invasion: Invasion of surrounding tissues outside of thyroid indicates biologic aggressiveness and significantly worsens the patient's prognosis

• Lymph node metastasis: Lymph node metastasis does not appear to be as important in the outcome of well-differentiated thyroid carcinomas as in the outcome of most other solid tumors

• Distant metastasis: Distant metastasis at initial examination is associated with a 68.1-fold increase in the rate of disease-specific death

• Socioeconomic factors: A study by Swegal et al indicated that socioeconomic factors affect survival in cases of well-differentiated thyroid cancer, with lower household income being associated with a higher disease-related death rate; the study included 1317 patients ^[29]

Clinical features

Hürthle cell carcinoma is a rare thyroid malignancy that is often considered a variant of follicular carcinoma. Also known as oncocytic carcinoma, Hürthle cell carcinoma has unique biologic features. About 75-100% of the tumor is composed of Hürthle cells, which are also known as oxyphilic, oncocytic, Askanazy, or large cells. These are large, polygonal follicular cells that contain abundant granular acidophilic cytoplasm. Hürthle cells can be found in a variety of benign thyroid conditions, such as Hashimoto thyroiditis, Graves disease, and multinodular goiter. Benign neoplasms, called Hürthle cell adenomas, that contain more than 75% Hürthle cells can also occur.

Hürthle cell carcinomas account for 2-3% of all thyroid malignancies. They occur more commonly in women than in men and typically manifest in the fifth decade of life. The clinical presentation is similar to that of other thyroid malignancies.

Pathology

On pathologic examination, Hürthle cell carcinoma, like follicular carcinoma, is differentiated from Hürthle cell adenoma by the presence of capsular invasion, vascular invasion, or both. On gross evaluation, Hürthle cell carcinomas appear brown and solid. Most have an appreciable capsule. Under microscopy, the tumors have a solid or trabecular growth pattern of large, granular, polygonal Hürthle cells.

Because malignant tumors are difficult to identify on the basis of cellular elements alone, Hürthle cell tumors identified on FNAB findings cannot be categorized as malignant or benign. Therefore, when FNAB results suggest a Hürthle cell neoplasm, a surgically obtained specimen is required.

Management

Hürthle cell carcinomas behave aggressively. Patients with these lesions are at high risk for recurrent and metastatic disease. These tumors most often do not take up radioactive iodine, thereby removing the diagnostic and therapeutic benefits that papillary and follicular carcinomas have. Most surgeons advocate an aggressive approach to treating these tumors. Patients with a diagnosis of Hürthle cell neoplasm based on FNAB findings undergo lobectomy and isthmectomy. If, the final pathologic result confirm Hürthle cell carcinoma, patients return to surgery for completion thyroidectomy. For tumors >5 cm or for palpable lymphatic metastases, total thyroidectomy (including neck dissection for palpable lymph nodes) is often performed during the initial operation.

Prognosis

Patients with Hürthle cell carcinoma should be monitored closely for recurrent and metastatic disease. The overall 5-year survival rate is 50-60%. Because tumors do not take up iodine and are not TSH sensitive, thyroid suppression and radioiodine therapy have little value. External-beam radiation therapy can used to treat metastatic disease. Surgery is the mainstay of treatment.

Clinical features

MTCs represent approximately 5% of all thyroid malignancies. A slight female preponderance is observed. Tumors arise from the parafollicular C cells of the thyroid gland. C cells are neural-crest derivatives and produce calcitonin. About 75% of MTCs occur sporadically, and 25% occur familially. Familial cases are commonly multifocal throughout the thyroid gland, whereas sporadic cases are usually not multifocal.

Patients may present with clinical evidence of MTC, or they may present before MTCs develop if they are from a family with known FMTC syndrome. New germline mutations can also occur. Patients with new germline mutations present with MTCs without a positive family history, but they are at risk for passing on the syndrome.

The FMTC syndromes consist of MEN 2A, MEN 2B, and FMTC. They are inherited in an autosomal dominant fashion. Children inheriting an FMTC syndrome have a 100% risk of developing MTC.

MEN 2A (Sipple syndrome) consists of MTC, pheochromocytoma (in 50% of patients), and hyperparathyroidism (10-20% of patients). MEN 2B consists of MTC, pheochromocytoma (in 50% of patients), marfanoid habitus, and ganglioneuromatosis. FMTC consists of MTC alone. MTC in MEN 2B has the most aggressive biologic features. In this situation, MTC usually develops by the age of 10 years, and it has a high propensity for rapid growth and metastasis. MTC in MEN 2A can appear in the first decade of life, and it almost always develops by the second decade. MTC in FMTC usually develops during adulthood.

Diagnosis of sporadic cases

Sporadic cases typically manifest with painless solitary thyroid nodules, like other thyroid malignancies do. Likewise, symptoms of pain, dysphagia, and hoarseness can develop with local invasion.

Genetic testing for MEN and FMTC

Genetic testing is now the mainstay in the diagnosis of the FMTC syndromes. RET proto-oncogene mutations (on chromosome arm 10q) have been discovered in each of the MTC syndromes. The RET proto-oncogene is a receptor tyrosine kinase whose exact function and role in these syndromes has not been elucidated. Patients with MEN 2A have germline RET mutations resulting in substitutions of conserved cysteine residues in exons 10 and 11. All patients with MEN 2B have a germline mutation resulting in a threonine-for-methionine substitution in codon 918 of exon 16. Mutations are described in exons 13 and 14 in patients with FMTC.

Genetic screening with sensitive PCR assays for germline RET mutations is routinely performed in at-risk patients. Children of parents known to have MEN or FMTC are tested for RET mutations to guide therapy and future genetic counseling. In addition, patients presenting with sporadic MTC should undergo RET mutational analysis to rule out new spontaneous germline mutations, which should prompt the testing of offspring for similar mutations.

Biochemical testing for MTC

Because MTC cells produce calcitonin, elevated serum calcitonin levels are diagnostic of MTC. Although routine measurement of serum calcitonin has low yield in managing the solitary thyroid nodule because of the uncommon nature of MTCs, it is useful in the surveillance of patients with a history of MTC and in managing familial forms. Stimulating calcitonin release by using intravenous pentagastrin increases the sensitivity of the test. For pentagastrin-stimulated calcitonin evaluation, a baseline plasma calcitonin level is measured, followed by the intravenous administration of pentagastrin 0.5 mg/kg and serial measurements of calcitonin 1.5 and 5 minutes after injection. Elevated basal or stimulated calcitonin levels above the normal range for the laboratory strongly suggest MTC.

Plasma calcitonin levels are commonly increased before clinical evidence of MTC appears. Although this finding was once the mainstay in diagnosing familial forms of MTC, results of genetic testing have largely supplanted it. Plasma calcitonin testing is now used for the early detection of MTC in patients already known to be at risk for MTC because of their family history and genetic results. This level is most commonly used as a tumor marker to identify residual and metastatic disease after thyroidectomy to treat MTC.

Pathology

On gross examination, MTCs are fairly well circumscribed, though they are unencapsulated. They are typically tannish pink and often contain yellow granular regions, which represent focal calcification. Most tumors arise in the middle and upper third of the thyroid lobes, commensurate with the location of the parafollicular C cells in the thyroid gland. Sporadic tumors are unilateral, and inherited forms usually involve both thyroid lobes.

MTCs can have a varied microscopic appearance. The tumors typically have a lobular, trabecular, insular, or sheetlike growth pattern. Some tumors have a fibrotic character. Malignant cells may appear round, polygonal, or spindle shaped. The cytoplasm is eosinophilic and finely granular. In the stroma, characteristic deposits of amyloid are commonly observed. This amyloid has typical green birefringence on Congo red staining, and this is a feature unique to MTC among thyroid malignancies. Immunohistochemical stains for calcitonin and carcinoembryonic antigen are microscopically useful for differentiating MTC from other tumors.

A unique feature to the familial cases of MTC is the finding of C-cell hyperplasia, which can help in distinguishing familial cases from sporadic ones. C-cell hyperplasia is considered a precursor to MTC and is usually adjacent to foci of MTC. The finding of C-cell hyperplasia with MTC should raise the suspicion for familial disease.

Treatment

The primary treatment for medullary thyroid carcinoma (MTC) is extensive and meticulous surgical resection. Both sporadic MTCs and FMTCs are treated with total thyroidectomy and lymphatic dissection of the anterior compartment of the neck (level VI). If the vasculature of the parathyroid gland is disrupted, autotransplantation of the parathyroid gland into the sternocleidomastoid muscle or the nondominant forearm is performed.

Metastasis to the cervical lymph nodes is common in patients with MTC, particularly those with familial forms with multicentricity and bilaterality of the primary tumor. Lymph node metastases can occur in more than 50% of patients. Both before and at the time of surgery, the lateral jugular lymphatics should carefully be palpated for evidence of metastatic disease. Selective neck dissection (sparing nonlymphatic structures when possible) of levels II, III, IV, and V is performed when metastases are clinically evident. 

Pharmacotherapy

RET tyrosine kinase inhibitors

Selpercatinib is the first targeted therapy to be approved by the US Food and Drug Administration (FDA) for tumors that have rearranged during transfection (RET) mutations. It is indicated for advanced or metastatic RET-mutant MTC in adults and children aged 12 years or older who require systemic therapy. 

Accelerated approval in May 2020 for MTC was based on the open-label LIBRETTO-001 phase I/II clinical trial (n = 143). Overall response rate (ORR) was 69% in cabozantinib/vandetanib treatment–experienced patients (n = 55) and 73% in treatment-naïve patients (n = 88). The phase III confirmatory trial (LIBRETTO-531) is under way. ^[30]   

Pralsetinib gained accelerated approval in December 2020 for adult and pediatric patients aged 12 years or older with advanced or metastatic RET-mutant MTC in whom systemic therapy is required and who are refractory to radioactive iodine (if radioactive iodine is appropriate).

The approval was based on outcomes from the phase I/II ARROW study, in which durable clinical activity was demonstrated whether or not patients had undergone prior therapy and regardless of RET-alteration genotypes. ^[31]  

Prophylactic thyroidectomy in patients with MEN 2A and MEN 2B

MTC is the most common cause of mortality in patients with MEN 2A and MEN 2B, and many patients who inherit these syndromes develop MTC in the first decade of life. Therefore, prophylactic thyroidectomy and central-compartment lymph-node dissection is being performed in children with these syndromes. Surgery is offered to patients when the diagnosis is made on the basis of RET mutational analysis. Children with RET mutations whose parents decline surgery should be monitored with annual measurement of calcitonin levels. Thyroidectomy is performed when results are abnormal.

Follow-up care

After receiving treatment for MTC, patients are monitored with annual measurement of serum calcitonin levels for surveillance. Pentagastrin-stimulated calcitonin testing is no longer widely available. Carcinoembryonic antigen is another tumoral marker associated with the recurrence of MTC, and it may also be used for surveillance. Patients with elevated levels of calcitonin or carcinoembryonic antigen are evaluated for recurrent disease. Neck, abdominal, and pelvic CT or MRI may be used to detect disease if metastasis or recurrence is suspected. Ultrasonography may be useful to localize cervical disease. In addition, radionuclide studies and selective venous catheterization with sampling of calcitonin levels can be performed to localize recurrences. The role of PET is evolving.

Radiation therapy is used in an adjuvant setting at some centers, and it can be used to treat patients with surgically inoperable recurrences and metastases. Because MTC does not concentrate iodine, radioiodine therapy has no role in follow-up care or treatment.

A variety of chemotherapeutic regimens have been used to treat metastatic disease. MTC is relatively insensitive to chemotherapy, though partial responses have been obtained. To date, the most effective combination is dacarbazine, vincristine, and cyclophosphamide. Adding doxorubicin to this regimen, some investigators have gained a partial response rate of about 35%.

Vandetanib (Caprelsa) and cabozantinib (Cometriq) are tyrosine kinase inhibitors approved by the FDA for progressive, metastatic medullary thyroid cancer. These agents target various tyrosine kinases, including MET, RET, and VEGFR-2.

Prognosis

The overall prognosis for patients with MTC is worse than that of patients with well-differentiated carcinoma. The reported 10-year survival rate is 65% overall. Young age, small primary tumor, low stage of disease, and completeness of initial resection improve survival. Patients with MEN 2B have a prognosis substantially worse than that of patients with MEN 2A, though the prognosis for both groups has improved with early diagnosis and intervention.

Anaplastic Thyroid Carcinoma

Clinical features

Anaplastic thyroid carcinoma is one of the least common thyroid carcinomas, accounting for 1.6% of all thyroid cancers. However, it has the most aggressive biologic behavior of all thyroid malignancies and one of the worst survival rates of all malignancies in general. Like papillary and follicular carcinomas, anaplastic thyroid carcinomas affect more women than men, with a female-to-male ratio of about 2-3:1. Patients with anaplastic thyroid carcinomas present later than those with other thyroid malignancies; the former most typically present in the sixth or seventh decade of life. ^[32]

Anaplastic thyroid carcinoma manifests as a rapidly growing thyroid mass in contrast to well-differentiated carcinomas, which are comparatively slow growing. Patients commonly present with associated symptoms due to local invasion. Hoarseness and dyspnea resulting from the involvement of the recurrent laryngeal nerve and airway occur in as many as 50% of patients.

Physical examination reveals a firm thyroid mass or masses that are most often larger than 5 cm at presentation. About 30% of patients have vocal cord paralysis, and cervical metastases are palpable on examination in 40% of patients. At least one half of patients already have distant metastases at the time of diagnosis. The most common sites of involvement are the lungs, bones, and brain.

Pathology

On gross examination, anaplastic thyroid carcinoma is a large and invasive tumor. Areas of focal necrosis and hemorrhage may be present throughout the tumor, giving a highly variable appearance. The tumor often extends through the capsule of the thyroid gland itself. Areas of well-differentiated thyroid carcinoma are often found concomitantly, and anaplastic thyroid carcinoma is believed to arise from a preexisting, well-differentiated thyroid carcinoma.

On microscopic evaluation, squamoid, spindle cell, and giant cell variants are observed. All 3 histologic variants show high mitotic activity, large foci of necrosis, and notable infiltration. Immunohistochemical stains are often positive for low-molecular-weight keratins and occasionally positive for thyroglobulin. Regarding their ultrastructure, the neoplasms have epithelial features (eg, desmosomes, tight junctions) that are helpful for differentiating them from sarcomas. Small cell carcinomas, which usually represent lymphomas, may be confused with anaplastic thyroid carcinoma.

Treatment

The progression of disease is rapid, and most patients die from local airway obstruction or complications of pulmonary metastases within 1 year despite all treatment efforts. Total or subtotal thyroidectomy is performed when the extent of the permits it. Neck dissection is added to manage palpable cervical metastases. Complete excision is often impossible because many patients present with clinically significant local extension. Tracheal and laryngeal resection is usually not performed to remove disease because of the poor prognosis in these circumstances. Tracheotomy is needed in cases with airway compromise due to tracheal invasion. External-beam irradiation is effective in improving local control. It is added postoperatively or used as primary treatment in unresectable cases. Chemotherapy is added for palliation. Doxorubicin is the most commonly used chemotherapeutic agent. Chemotherapy and radiation therapy typically administered used in combination.

In May 2018, dabrafenib used in combination with trametinib became the first FDA-approved treatment for locally advanced or metastatic anaplastic thyroid cancer with BRAF V600E mutation in patients with no satisfactory alternatives for locoregional therapy. Approval came following a nine-cohort, multicenter, nonrandomized, open-label trial involving patients with BRAF V600E mutation–positive cancer. Investigators found that 57% of patients with anaplastic thyroid cancer experienced a partial response to the treatment, and 4% had a complete response. Sixty-four percent of the patients who responded suffered no significant tumor growths for at least 6 months. ^{[33, 34]}

Prognosis

Anaplastic thyroid carcinoma is poorly responsive to multimodality therapy, and median survival is 8.1 months. Young age, unilateral tumors, small tumors (< 5 cm), no local invasion of the surrounding tissue, and a lack of cervical metastases are relatively favorable prognostic indicators. Patients with these features may have slightly prolonged survival. Long-term survival should prompt a reconsideration of the diagnosis of anaplastic thyroid carcinoma; the original tumor is usually found to be a variant of MTC or thyroid lymphoma.

Primary Thyroid Lymphoma

Clinical features

Primary lymphomas of the thyroid gland represent approximately 2-5% of all thyroid malignancies. Most thyroid lymphomas are non-Hodgkin B-cell tumors. The next most common histologic type is low-grade malignant lymphoma of mucosa-associated lymphoid tissue (MALT). Hodgkin lymphoma, Burkitt cell lymphoma, and T-cell lymphoma have also been reported.

The incidence peaks in the sixth decade of life, and most diagnoses are made in patients aged 50-80 years. Women are more commonly affected than men, with a female-to-male ratio of 4:1. This tumor is highly associated with chronic lymphocytic thyroiditis (Hashimoto thyroiditis). Almost all patients with primary thyroid lymphoma have either a clinical history or histologic evidence of chronic lymphocytic thyroiditis. The risk of primary thyroid lymphoma increases 70-fold in patients with chronic lymphocytic thyroiditis compared with the general population.

The most common clinical presentation is an enlarging thyroid mass. Patients may have clinical or serologic evidence of hypothyroidism. Local extension into the aerodigestive tract or surrounding tissues may cause dysphagia, dyspnea, or symptoms of pressure in the neck. Vocal fold paralysis and hoarseness suggest involvement of the recurrent laryngeal nerve. Regional and distant lymphadenopathy is common.

Diagnosis is based on the patient's clinical presentation with a positive tissue diagnosis. FNAB may be useful for diagnosing thyroid lymphoma, but it is considered less reliable with this lesion than with other thyroid malignancies. Lymphoma may be difficult to differentiate from chronic lymphocytic thyroiditis. Surgical biopsy of the lesion is preferred for diagnosing thyroid lymphoma. Biopsy enables thorough histochemical and immunohistochemical analysis to confirm the diagnosis. Tumor cells are positive for leukocyte-common antigen and for B- or T-cell markers depending on the type of tumor.

Staging of thyroid lymphomas is important for therapeutic and prognostic purposes. Staging involves CT scanning of the brain, neck, chest, abdomen, and pelvis, as well as bone marrow biopsy. Most primary thyroid lymphomas are localized to the thyroid gland alone and, therefore, classified as stage IE (localized to an extranodal site). Involved regional lymph nodes increase the stage to IIE.

Treatment and prognosis

Stage IE lymphomas may be treated with total thyroidectomy followed by postoperative radiation therapy. Surgical excision should not be performed if local infiltration into surrounding tissues is evident. Stage IIE lymphomas are treated with combined chemotherapy and radiation therapy. Doxorubicin or CHOP (ie, cyclophosphamide, hydroxydaunomycin, Oncovin [vincristine], prednisone) is the commonly used chemotherapeutic regimen.

Most thyroid lymphomas are stage IE, which have a 5-year survival rate of up to 85%. Spread beyond the thyroid gland reduces the 5-year survival rate to about 35%. Lymphomas at stages higher than this worsen the prognosis.

Sarcoma of the Thyroid Gland

Sarcomas that arise in the thyroid gland are uncommon. They are aggressive tumors that most likely arise from stromal or vascular tissue in the gland. Malignancies that appear to be sarcomas should be differentiated from anaplastic thyroid carcinomas, which can appear sarcomatous.

The treatment for thyroid sarcomas is total thyroidectomy. Radiation therapy may be used in an adjunctive setting. Most sarcomas are unresponsive to chemotherapy. Recurrence is common, as it is with sarcomas arising in other sites in the body, and the patient's overall prognosis is poor.

Thyroid surgery is performed to diagnose or treat thyroid disease. The extent of surgery ranges from isthmectomy alone (for small nodules truly localized to the isthmus) to subtotal thyroidectomy, total thyroidectomy, or extended thyroidectomy. Radioiodine studies performed after total thyroidectomy usually show residual normal thyroid tissue despite total thyroidectomy.

Principles of thyroid surgery are accurate execution of the planned excision, avoidance of injury to the recurrent laryngeal nerve, avoidance of injury to or devascularization of the parathyroid glands, and meticulous hemostasis.

Indications

See the list below:

• Indications for thyroid lobectomy

  • Biopsy of a solitary thyroid nodule suggestive of malignancy

  • Management of compressive or cosmetic symptoms due to a multinodular goiter

  • Management of a well-differentiated thyroid carcinoma in a low-risk patient (This is controversial.)

• Indications for total thyroidectomy

  • Management of a well-differentiated thyroid malignancy

  • Management of an MTC

  • Management of a sarcoma of the thyroid gland

  • Management of stage I_E thyroid lymphoma

  • Management of an obstructive goiter (Consider subtotal thyroidectomy.)

Preoperative considerations

Vocal fold mobility should always be determined before thyroid surgery. If lobectomy for biopsy is planned, discuss the potential need for completion thyroidectomy with the patient.

Operative technique

Positioning of the patient is important. Place the patient in a supine position with his or her neck extended by using a shoulder roll. Plan a horizontal incision in a natural skin crease to contour the curvature of the neck. The location should overlie the thyroid gland, evenly extending between the anterior aspect of the sternocleidomastoid muscles on both sides.

Elevate skin flaps superiorly and inferiorly in a subplatysmal plane. (Platysma is often absent in the midline.) Ligate the anterior jugular veins only if they directly limit exposure. Separate the sternohyoid and sternothyroid muscles in the median raphe, and retract them laterally to expose the cricoid cartilage and thyroid isthmus.

In the anterior region, dissect the strap muscles off the face of the thyroid lobe (bilaterally for total thyroidectomy). Supracapsular dissection is continued until the superior pole and its vascular pedicle are isolated. The superior pole vessels are divided and ligated. The dissection continues laterally with division of the middle thyroid vein. The thyroid lobe is gradually medialized. Careful blunt dissection is performed to identify the recurrent laryngeal nerve in the tracheoesophageal groove.

After the recurrent nerve is identified, carefully follow the nerve superiorly toward the larynx. The nerve passes closely to the Berry ligament, but its position varies. After the nerve is thoroughly identified in this region, divide the ligament to release the thyroid gland.

Keep the location of the parathyroid glands in mind during lateral dissection. Avoid disturbing the gland and vasculature as much as possible. Dissection close to the thyroid capsule minimizes this risk. If possible, ligate the inferior thyroid artery only after the vessels to the inferior parathyroid gland branch.

If a parathyroid gland is inadvertently removed, reimplant it in the sternocleidomastoid muscle or on the volar surface of the forearm after slicing it into small pieces and marking it with a surgical clip.

During superior dissection, remember the nearby location of the external branch of the superior laryngeal nerve, which innervates the cricothyroid muscle. Ligation of the superior-pole vessels tight to the thyroid in this area avoids inadvertent injury to this nerve.

If only lobectomy is planned, divide the thyroid isthmus in the midline. Ligate the final soft-tissue attachments, and remove and label the lobe. Send it to the pathology laboratory. When total thyroidectomy is performed, the surgeon may elect not to divide the thyroid isthmus in the midline, but rather, to perform lateral dissection bilaterally. Identify the recurrent laryngeal nerves, and manage the inferior and superior vascular pedicles similarly. Remove the gland in 1 piece, label it, and send it for pathologic analysis.

Irrigate the wound, and achieve meticulous hemostasis. The decision to place a passive or closed suction drain often depends on the surgeon's judgment. If a drain is used, place it into the wound and bring it out laterally through the incision or through a separate stab incision. The present authors have found the routine use of drains unnecessary. Reapproximate the sternothyroid and sternohyoid, and carefully close the skin in layers.

A study by Salari et al of 35 patients with advanced thyroid malignancy and extensive nodal disease suggested that in such cases, a neural-monitored, staged surgical approach can safely and effectively be used in place of a simultaneous bilateral operation. ^[35]

Postoperative care

If a surgical drain is placed, maintain it until its output has diminished sufficiently, usually on the first postoperative day. Hypocalcemia may occur in patients who have undergone total thyroidectomy. Assess for hypocalcemia by inquiring about perioral paraesthesia. In a patient with hypocalcemia, tapping on preauricular region overlying the trunk of the facial nerve may cause ipsilateral contraction of the face (Chovstek sign). Measure ionized calcium postoperatively. Hypocalcemia may require calcium and vitamin D supplementation. Manage pain with acetaminophen and narcotics as needed.

Organizations that have released guidelines for the diagnosis and/or management of thyroid cancer include the following:

• American Thyroid Association (ATA) ^{[1, 36, 37]}
• National Comprehensive Cancer Network (NCCN) ^[38]
• American Association of Clinical Endocrinologists/American College of Endocrinology/Associazione Medici Endocrinologi (AACE/ACE/AME) ^[39]  

A study by Ha et al comparing the sensitivity and specificity of guidelines providing ultrasonography-based fine-needle aspiration biopsy (FNAB) criteria found that guidelines from the Korean Thyroid Association/Korean Society of Thyroid Radiology (KTA/KSThR), National Comprehensive Cancer Network (NCCN), and American Thyroid Association (ATA) were more sensitive (94.5%, 92.5%, 89.6%, respectively) than were guidelines released by the American Association of Clinical Endocrinologists/ American College of Endocrinology/Associazione Medici Endocrinologi (AACE/ACE/AME), American College of Radiology (ACR), French Society of Endocrinology (FSE), and Society of Radiologists in Ultrasound (SRU) (80.4%, 74.7%, 72.7%, 70.9%, respectively). At the same time, the latter four sets of guidelines were more specific than were those from KTA/KSThR, NCCN, and ATA. The report also found that among the seven sets of guidelines, those from the ACR led to the lowest rate of unnecessary FNABs (25.3%). ^[40]

Diagnosis

All the guidelines advocate ultrasonographic (US) evaluation of thyroid nodules along with measurement of serum thyroid-stimulating hormone (TSH) levels to determine whether a fine needle aspiration biopsy (FNAB) is indicated. A routine measurement of serum thyroglobulin (Tg) for the initial evaluation of thyroid nodules is not recommended because Tg levels are elevated in most benign thyroid conditions. ^{[1, 39, 38]}

Although all the guidelines recommend FNAB as the procedure of choice in the evaluation of solid thyroid nodules, there is variance in the size of the nodule as an indication for FNAB, as follows ^{[1, 39, 38]} :

ATA ^[1]

Guidelines include the following for FNAB:

• Nodules ≥1cm with high or intermediate risk US features
• Nodules ≥1.5 cm with low risk US features
• Nodules ≥2 cm with very low risk US features, consider FNAB; observation is a reasonable alternative

AACE/ACE/AME ^[39]

Guidelines include the following for FNAB:

• US high-risk nodules ≥1 cm
• US intermediate-risk nodules >2 cm
• US low-risk nodules only when >2 cm and increasing in size or associated with a risk history and before thyroid surgery or minimally invasive ablation therapy

NCCN ^[38]

Guidelines include the following for FNAB:

• Nodules >1 cm if suspicious US features are present
• Nodules >1.5 cm if no suspicious US features are present

AACE/ACE/AME and NCCN suggest a serum calcitonin assay as an optional test, ^{[39, 38]}  but the ATA guidelines make no recommendation on the routine measurement of serum calcitonin because of insufficient evidence. ^[1]  All three guidelines recommend radionuclide imaging in patients with a low TSH level. ^{[1, 39, 38]}

Differentiated thyroid cancers

ATA guidelines state that FNAB provides the most economical and accurate methodology for diagnosing differentiated thyroid cancers. Due to potential false negatives or sampling error, it is recommended that FNAB procedures be performed under US guidance. US guidance is particularly important for nodules located posteriorly and for those that are difficult to palpate. Additionally, certain features found on US examination are predictive for malignancy and may guide FNAB decision-making. ^[1]  

Papillary thyroid cancer is characterized by the following US features:

• Solid or predominantly solid
• Hypoechoic
• Microcalcifications (highly specific)
• Infiltrative irregular margins (common)
• Increased nodular vascularity

Follicular thyroid cancer is characterized by the following US features:

• Isoechoic to hyperechoic
• Thick, irregular halo

Benign US features are as follows:

• Purely cystic nodule
• Spongiform appearance (aggregation of multiple microcystic components >50% volume)

Malignancy risk

Cytologic analysis of FNAB specimens is used to estimate malignancy risk. The most appropriate cytologic classification of malignancy risk is the Bethesda system for thyroid cytopathology, which includes the following categories ^{[41, 42]} :

• Nondiagnostic or unsatisfactory (risk 5-10%)
• Benign (risk 0-3%)
• Atypia of undetermined significance or follicular lesion of undetermined significance (risk ∼10-30%)
• Follicular neoplasm or suspicious for follicular neoplasm (risk 25-40%)
• Suspicious for malignancy (risk 50-75%)
• Malignant (risk 97-99%)

A 2017 revision to the Bethesda system includes a second set of malignancy risks for these six categories, one that calculates what these risks would be if noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP) were not classified as a malignancy. The adjusted risks for the six categories would be as follows ^{[42, 43]} :

• Nondiagnostic or unsatisfactory (risk 5-10%)
• Benign (risk 0-3%)
• Atypia of undetermined significance or follicular lesion of undetermined significance (risk 6-18%)
• Follicular neoplasm or suspicious for follicular neoplasm (risk 10-40%)
• Suspicious for malignancy (risk 45-60%)
• Malignant (risk 94-96%)

For cytology “diagnostic of” or “suspicious for” papillary thyroid cancer, surgery is recommended. ^[1]

If FNAB cytology is indeterminate, the use of molecular markers such as BRAF, RAS, RET/PTC, Pax8-PPARɣ, or galectin-3 may be considered to guide management. ^[1]

An iodine-123 (¹²³I) thyroid scan may be considered if the cytology report documents a follicular neoplasm, especially if serum thyroid-stimulating hormone (TSH) is in the low-normal range. ^[1] No radionuclide scan is needed for a reading of “suspicious for papillary carcinoma” or “Hürthle cell neoplasm”, as either lobectomy or total thyroidectomy is recommended depending on the nodule size and risk factors. ^[1]

The NCCN recommends that FNAB should be the primary test for differentiated thyroid cancer. If FNAB reveals papillary carcinoma, follicular neoplasm, follicular lesion of undetermined significance, or Hürthle cell neoplasm, the following diagnostic recommendations should be undertaken (these are uniform for all differentiated thyroid carcinomas) ^[38] :

• Thyroid and neck ultrasonography (including central and lateral compartments) if not previously done
• Computed tomography (CT) scanning/magnetic resonance imaging (MRI) for fixed, bulky, or substernal lesions (iodinated contrast optimal for cervical imaging)
• Consider evaluation of vocal cord mobility

Medullary thyroid carcinoma

Patients with medullary thyroid carcinoma can be identified by pathologic diagnosis or by prospective genetic screening. According to the revised ATA guidelines, an FNAB result suspicious for medullary thyroid carcinoma should prompt the following ^[36] :

• Ultrasonography of the neck
• Serum calcitonin assay
• Serum carcinoembryonic antigen (CEA) measurement
• DNA analysis for  RET germline mutation

According to 2009 ATA guidelines, a calcitonin level >100 pg/mL should be considered suspicious of medullary thyroid carcinoma. ^[44] Although calcitonin is a valuable tumor marker in patients with medullary thyroid carcinoma, the 2015 revised ATA guidelines note that clinical judgment should be exercised in the interpretation of calcitonin test results. Serum levels can be falsely high or low in a variety of clinical diseases, can be elevated in children under 3 years of age, and can be higher in males than females. ^[36]

The NCCN recommends the following diagnostic procedures when FNAB results indicate medullary thyroid carcinoma ^[38] :

• Basal serum calcitonin level
• CEA level
• Pheochromocytoma screening
• Serum calcium assay
• Consider genetic counseling
• Screen for  RET proto-oncogene mutations (exons 10, 11, 13-16)
• Thyroid and neck ultrasonography (including central and lateral compartments), if not previously done
• Consider evaluation of vocal cord mobility
• Consider contrast-enhanced CT scan of chest and mediastinum or MRI scan if N1 disease or calcitonin >400 pg/mL

Treatment of Differentiated Thyroid Cancers

The treatment of choice for differentiated thyroid cancers is surgery, whenever possible, followed by radioiodine (¹³¹I) in selected patients and thyrotropin suppression in most patients, according to the National Comprehensive Cancer Network (NCCN) guidelines. ^[38]

Papillary thyroid carcinoma

NCCN guidelines recommend total thyroidectomy for patients who meet any of the following criteria ^[38] :

• Radiation history
• Known distant metastases
• Bilateral nodularity
• Extrathyroidal extension
• Tumor >4 cm in diameter
• Cervical lymph node metastases
• Poorly differentiated tumor

The NCCN considers either total thyroidectomy or lobectomy to be acceptable for patients who meet all of the following criteria ^[38] :

• No prior radiation
• No distant metastases
• No cervical lymph node metastases
• No extrathyroidal extension
• Tumor < 4 cm in diameter

If a lobectomy is performed, completion of the thyroidectomy is recommended for any of the following ^[8] :

• Tumor >4 cm in diameter
• Positive margins
• Extrathyroidal extension
• Macroscopic multifocal disease
• Macroscopic nodal metastases
• Confirmed contralateral disease
• Vascular invasion

ATA guidelines recommend near-total or total thyroidectomy for all patients with thyroid cancer greater than 1 cm, unless there are contraindications to this surgery. Lobectomy may be considered for small (< 1 cm), low-risk, thyroidal papillary carcinomas in the absence of prior radiation or clinically involved cervical nodal metastases. ^[1]

Both the NCCN and ATA recommend that therapeutic neck dissection for patients with clinically involved central or lateral neck lymph nodes should accompany total thyroidectomy to provide clearance of disease from the central neck. Prophylactic central-compartment neck dissection (level VI) may be considered in patients with clinically uninvolved central neck lymph nodes, especially for advanced primary tumors (T3 or T4). ^{[1, 38]}

Follicular thyroid cancer and Hürthle cell carcinoma

The ATA does not have comprehensive guidelines for the treatment of follicular thyroid cancer (FTC) and Hürthle cell carcinoma as separate entities from papillary thyroid cancer; however, there are several individual recommendations that apply decision-making principles to these conditions. ^[1]

The ATA recommends that if cytology readings report a follicular neoplasm, an ¹²³I thyroid scan may be considered, especially if serum TSH is in a low-normal range. If a concordant autonomously functioning nodule is not seen, lobectomy or total thyroidectomy should be considered.

If the cytology report indicates “Hürthle cell neoplasm” or “suspicious for papillary carcinoma,” the ATA recommends a lobectomy or thyroidectomy, depending on nodule size and other risk factors.

For patients with an isolated indeterminate (“follicular neoplasm” or “Hürthle cell neoplasm”) solitary nodule who prefer a more limited approach, the ATA recommends an initial lobectomy.

The ATA recommends a total thyroidectomy for patients with indeterminate nodules in any of the following situations:

• The tumor exceeds 4 cm
• Marked atypia is observed
• Biopsy result is reported as “suspicious for papillary carcinoma”
• The patient has a family history of thyroid carcinoma
• The patient has a history of radiation exposure

The ATA recommends that patients with indeterminate nodules who have bilateral nodular disease or who wish to avoid future surgery should undergo total or near-total thyroidectomy. ^[1]

The NCCN guidelines recommend lobectomy plus isthmusectomy as the initial surgery for patients with follicular neoplasms and Hürthle cell carcinomas, with prompt completion of thyroidectomy if invasive cancer is found on the final histologic section. Therapeutic neck dissection of involved compartments is recommended for clinically apparent/biopsy-proven disease.

The NCCN recommends total thyroidectomy as the initial procedure only if invasive cancer or metastatic disease is apparent at the time or surgery, or if the patient wishes to avoid a second, completion thyroidectomy should the pathologic review reveal cancer. ^[38]

Radioiodine therapy

NCCN guidelines recommend radioiodine (¹³¹I) therapy if any of the following are present ^[38] :

• Extrathyroidal extension
• Tumor >4 cm in diameter
• Postoperative unstimulated Tg level >5-10 ng/mL

Radioiodine therapy is not recommended if all of the following are present ^[38] :

• Classic papillary thyroid carcinoma
• Primary tumor < 1 cm
• Intrathyroidal tumor
• Unifocal or multifocal tumor
• No detectable anti-Tg antibodies
• Postoperative unstimulated Tg < 1 ng/mL

Radioiodine therapy is selectively recommended if any of the following is present when the combination of clinical factors predicts a significant risk of recurrence ^[38] :

• Primary tumor 1-4 cm
• High-risk histology
• Lymphovascular invasion
• Cervical lymph node metastases
• Macroscopic multifocality (one focus >1 cm)
• Presence of anti-Tg antibodies
• Postoperative unstimulated Tg < 5-10 ng/mL

The ATA recommends radioiodine therapy for all patients if any of the following is present ^[1] :

• Distant metastases
• Extrathyroidal extension of the tumor regardless of tumor size
• Primary tumor size >4 cm even in the absence of other higher-risk features.

Radioiodine therapy is not recommended for patients with unifocal cancer under 1 cm without other higher-risk features or for patients with multifocal cancer when all foci are under 1 cm in the absence of other higher-risk features. ^[1]

Radioiodine therapy is also recommended for selected patients with 1-4 cm thyroid cancers confined to the thyroid who have documented lymph node metastases or other higher-risk features, when the combination of age, tumor size, lymph node status, and individual histology predicts an intermediate to high risk of recurrence or death from thyroid cancer. ^[1]

The ATA and NCCN guidelines recommend treatment with levothyroxine to suppress TSH levels. Degree of suppression is based on risk, as follows ^{[1, 38]} :

• Low-risk patients - Maintenance of the TSH at or slightly below the lower limit of normal (0.1-0.5 mU/L)
• Intermediate-risk patients - Initial TSH suppression to below 0.1 mU/L
• High-risk patients - Initial TSH suppression to below 0.1 mU/L

Treatment of Medullary Thyroid Cancer

The National Comprehensive Cancer Network (NCCN) guidelines recommend total thyroidectomy and bilateral central neck dissection (level VI) for all patients with medullary thyroid carcinoma whose tumor is 1 cm or greater or who have bilateral thyroid disease, as well as the following ^[38] :

• Therapeutic ipsilateral or bilateral modified neck dissection for clinically or radiologically identifiable disease (levels II–V)
• Prophylactic ipsilateral modified neck dissection for high-volume or gross disease in the adjacent central neck may be considered

External beam radiation therapy (EBRT) is an option for treatment of incomplete tumor resection when further surgical resection is no longer possible. EBRT can also be considered for adjuvant treatment of extrathyroidal extension (T4a or T4b) with positive margins.

Other therapy considerations are as follows:

• Total thyroidectomy is recommended and neck dissection can be considered for those whose tumor is < 1 cm and for unilateral thyroid disease
• Radioiodine (131I) therapy is not effective
• Suppression of TSH is not appropriate; TSH is kept in the normal range by adjusting levothyroxine dose
• Pheochromocytoma removal prior to thyroid surgery by laparoscopic adrenalectomy, and treatment preoperatively with alpha-adrenergic blockade (phenoxybenzamine) or with alpha-methyltyrosine to avoid a hypertensive crisis during surgery

Treatment of Anaplastic Thyroid Cancer

No curative treatment currently exists for anaplastic thyroid cancer. The majority of patients present with unresectable or metastatic disease. NCCN guidelines recommend attempting total thyroidectomy in patients with resectable disease. ^[38]

The 2012 ATA guidelines recommend total lobectomy or total or near-total thyroidectomy with a therapeutic lymph node dissection for patients with intrathyroidal anaplastic thyroid cancer. In patients with extrathyroidal invasion, an en bloc resection should be considered if grossly negative margins (R1 resection) can be achieved. ^[37]  Both the NCCN and ATA guidelines recommend adjuvant radiation therapy, chemotherapy, or both. ^{[37, 38]}

JAES Guidelines

The Japan Association of Endocrine Surgeons (JAES) has developed and published updated clinical practice guidelines on the management of thyroid tumors. ^[45]

Papillary thyroid carcinoma

The management of papillary thyroid carcinoma (PTC) should be based on risk classification: very low–risk, low-risk, intermediate-risk, and high-risk.

Total thyroidectomy is recommended for high-risk PTC but not for very low– and low-risk PTC (T1N0M0). As for intermediate-risk PTC, the extent of thyroidectomy chosen should be based on prognosis and patient background characteristics.

Prophylactic central lymph node dissection is recommended in the surgical treatment of PTC. For low-risk PTC, prophylactic lateral lymph node dissection is not recommended. As for intermediate- and high-risk PTC, the decision to perform prophylactic lateral node dissection should be based on the patient’s prognostic factors, background, and decision.

Nonsurgical active surveillance is recommended for very low-risk PTC in patients without evidence of metastasis or extension (T1aN0M0) after an adequate explanation of disease condition and the benefits and risks of management are provided to the patient.

Follicular thyroid carcinoma

Total thyroidectomy and radioactive iodine (RAI) therapy are recommended for widely invasive follicular thyroid carcinoma (FTC) with distant metastasis (M1). Completion total thyroidectomy is recommended for widely invasive FTC without distant metastasis (M0) diagnosed after lobectomy.

Completion total thyroidectomy is not uniformly recommended for M0 minimally invasive FTC after lobectomy.

Medullary thyroid carcinoma

All patients with medullary thyroid carcinoma (MTC) should undergo RET gene mutation analysis.

Prophylactic total thyroidectomy is not uniformly recommended for carriers of RET mutations who have not developed MTC.

Although the lesion is limited to one lobe, total thyroidectomy is recommended for hereditary MTC since the bilateral C cells may become cancerous.

Prophylactic central node dissection is also recommended for MTC.

Poorly differentiated carcinoma

Total thyroidectomy, prophylactic lymph node dissection, and RAI therapy are recommended for poorly differentiated carcinoma.

Anaplastic thyroid carcinoma

After curative surgery for anaplastic thyroid carcinoma (ATC) is performed, adjuvant therapies are recommended.

Multidisciplinary treatment is recommended for unresectable ATC.

For a recurrent lesion diagnosed as ATC in a patient with differentiated thyroid carcinoma (DTC), a treatment strategy for ATC is recommended.

Palliative care is recommended for ATC.

Radiation therapy

Postoperative adjuvant RAI therapy is recommended for high-risk PTC without distant metastasis (M0). Postoperative ablative RAI therapy is considered for intermediate-risk PTC after the patient’s prognostic factors are considered. Postoperative ablative RAI therapy is not recommended for low-risk PTC. Postoperative ablative or adjuvant RAI therapy is recommended for widely invasive FTC without distant metastasis (M0). Postoperative ablative RAI therapy is not recommended for minimally invasive FTC.

Iodine restriction is recommended for improving the accumulation of RAI to the normal remnant thyroid or malignant thyroid tissue.

Appropriate doses of RAI for RAI therapy are as follows:

• 1.1 GBq (30 mCi) for ablative RAI therapy
• 3.7-5.6 GBq (100-150 mCi) for adjuvant RAI therapy
• 3.7-7.4 GBq (100-200 mCi) for treatment

The decision for RAI therapy to treat recurrent differentiated thyroid carcinoma should be made after disease progression and location, number, and size of recurrent lesions are thoroughly considered. RAI therapy is strongly recommended for lung metastasis and bone metastasis. It is weakly recommended for either local recurrence or lymph node metastasis that is inoperable but requires therapy. RAI therapy is not recommended for brain metastasis, for metastasis to organs other than those already mentioned, or for patients without apparent recurrence but with high thyroglobulin levels.

Recombinant human thyroid-stimulating hormone (rhTSH) to increase thyrotropin levels at the time of RAI administration is recommended as a substitute for levothyroxine withdrawal before I-131 whole-body scan (WBS), serum thyroglobulin test, and ablation.

Extra beam radiotherapy is recommended in patients with symptoms due to advanced or recurrent thyroid carcinoma, since salvage surgery, RAI therapy, and molecular target drugs are not indicated.

Advanced differentiated carcinoma

In patients with preoperative nerve paralysis, resection of the invaded recurrent laryngeal nerve is recommended. Preservation of the nerve is recommended in patients without preoperative nerve paralysis.

Nerve reconstruction is recommended at the same time as the nerve resection.

Resection of the invaded tracheal wall is recommended and should be tailored based on disease stage, extension of tumor spread, risk of surgical complications, anticipated postoperative quality of life, prognosis, and skill of the treatment team.

Postoperative therapy (including for recurrence and metastasis)

For intermediate-risk PTC, the decision for TSH suppression therapy should be based on intraoperative and pathological findings. TSH suppression therapy is recommended for high-risk PTC and widely invasive FTC.

Cytotoxic chemotherapy is not recommended for advanced or recurrent DTC.

Alternative medicine is not recommended because of its unproven effectiveness in antitumor activity or survival benefit in patients with thyroid cancer.

Molecular target medicine therapy

Molecular target medicine is recommended for progressive DTC that is refractory to RAI therapy.

Molecular target medicine is recommended for progressing advanced or recurrent MTC.

Molecular target medicine (lenvatinib) is also recommended for unresectable advanced or recurrent ATC.