Follicular Thyroid Carcinoma

Practice Essentials

Follicular thyroid carcinoma (FTC) is the second most common cancer of the thyroid, after papillary carcinoma. Follicular and papillary thyroid cancers are considered to be differentiated thyroid cancers; together they make up 95% of thyroid cancer cases.^[1]

FTC and other thyroid neoplasms arising from follicular cells (adenomas, papillary/follicular carcinoma, and noninvasive follicular thyroid neoplasm with papillary-like nuclear features [NIFTP]) show a broad range of overlapping clinical and cytologic features. FTC resembles the normal microscopic pattern of the thyroid, and a clear distinction between benign and malignant disease based solely on cytologic examination of a needle biopsy specimen may be difficult.

For that reason, a surgical procedure to remove all or a large portion of the thyroid gland may be necessary to obtain sufficient tissue for a definitive diagnosis of FTC. Pathological examination showing capsular or vascular invasion may be required for this determination.

Papillary/follicular carcinoma must be considered a variant of papillary thyroid carcinoma (mixed form). Hurthle cell carcinoma (oncocytic thyroid carcinoma) had previously been considered a variant of FTC, but the World Health Organization (WHO) has reclassified it as a distinct entity.^[2]

Despite its well-differentiated characteristics, FTC may be minimally invasive, encapsulated angioinvasive, or widely invasive.^[2] In fact, FTC tumors may spread easily to other organs. About 11% of patients with FTC have metastases beyond the cervical or mediastinal area on initial presentation

FTC is more likely than papillary thyroid cancer to metastasize to lung and boner. The bone metastases in FTC are osteolytic. Risk of developing bone and lung metastases is greater in patients with FTC who are older than 45 years.

Current National Comprehensive Cancer Network (NCCN) guidelines recommend lobectomy plus isthmusectomy as the initial surgery for patients with follicular neoplasms, with prompt completion of thyroidectomy if invasive FTC 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 of surgery, or if the patient wishes to avoid a second, completion thyroidectomy should the pathologic review reveal cancer.^[3]

If all gross disease cannot be resected, or if residual disease is not avid for radioactive iodine, radiation therapy is often employed for locally advanced disease. Similarly, radiation therapy is indicated for unresectable disease extending into adjacent structures. Chemotherapy may be considered in symptomatic patients with recurrent or progressive disease. It could improve quality of life in patients with bone metastases. A number of targeted agents—in particular, tyrosine kinase inhibitors—have become available for treatment of disease refractory to radioiodine therapy.

For patient education information, see What Is Thyroid Cancer?. Patient education information on thyroid cancer is also available on the American Cancer Society Web site.

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Pathophysiology

The molecular pathogenesis of follicular thyroid carcinoma (FTC) is thought to be initiated by point mutations that result in dysregulation of the phosphatidylinositol-3 kinase (PI3K)/AKT signaling pathway. Dysregulation of PI3K/AKT can be triggered by activating mutations in a variety of genes, including RAS, PIK3CA, and AKT1, as well as by inactivation of PTEN.^[4]

Activating point mutations in RAS oncogenes are well known in follicular adenoma and carcinoma,^[5] especially in poorly differentiated (55%) and anaplastic carcinoma (52%). Mutations in NRAS have been reported in 17% to 57% of FTCs; mutations in KRAS and HRAS are less often found. PAX8/PPARG gene fusion, which results in production of a PAX8-PPARγ fusion protein, has been identified in approximately one-third of FTC cases (range, 12% to 53%). Activating mutations in TERT, which encodes telomerase reverse transcriptase, have been described in about 15% of FTCs and are associated with the worst clinical features and prognosis. TSH receptor mutations have been found in 10.3% of FTC cases; these appear to be mutually exclusive with RAS mutations.^{[4, 6]}

Some molecules that physiologically regulate the growth of thyrocytes, such as interleukins (IL-1 and IL-8) or other cytokines (IGF1, TGF-beta, EGF) could play a role in the pathogenesis of FTC.

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Etiology

The thyroid is particularly sensitive to the effects of ionizing radiation. Exposure to ionizing radiation results in a 30% risk for thyroid cancer.

A history of exposure of the head and neck to x-ray beams, especially during childhood, has been recognized as an important contributing factor to the development of thyroid cancer.

Seven percent of the individuals exposed to the atomic bomb blasts in Japan developed thyroid cancers. However, exposure to fallout from the Chernobyl nuclear accident was asssociated with increases in papillary rather than follicular thyroid carcinoma.^{[7, 8]}

From the 1920s to the 1960s, irradiation was used to treat tumors and benign conditions, such as acne; excessive facial hair; tuberculosis in the neck; fungal diseases of the scalp; sore throats; chronic coughs; and enlargement of the thymus, tonsils, and adenoids. About 10% of individuals who were treated with irradiation developed thyroid cancer after a latency period of 30 years.

Patients who receive radiotherapy for certain types of cancer of the head and neck area also may have an increased risk of developing thyroid cancer.

Exposure to diagnostic x-rays does not increase the risk of developing thyroid cancer.

Although follicular cancer is frequently present in goitrous thyroids, the relationship between prolonged elevation of thyroid-stimulating hormone (TSH) and follicular carcinoma is not known. Several reports have shown a relationship between iodine deficiency and the incidence of thyroid carcinoma, and rates of FTC decreased in geographic areas of endemic goiter after iodized salt was introduced.

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Epidemiology

Frequency

United States

The American Cancer Society (ACS) estimates that in 2024, 44,020 new thyroid cancers will occur, 31,520 in women and 12,500 in men; the ACS estimates that 2170 deaths from thyroid cancer will occur, 1180 in women and 990 in men. In women, thyroid cancer is the eighth most common cancer, accounting for approximately 3% of all new cases.^[9] In the United States, about 10-15% of all thyroid cancers are follicular.

International

Thyroid cancers account for 1.5% of all cancers in adults and 3% in children. The European Network of Cancer Registries reports that the incidence varies from country to country: Lithuania reported the highest age-standardized rate per 100,000 population (15.5), followed by Italy (13.5), Austria (12.4), Croatia (11.4), and Luxembourg (11.1).^[10] ​ The highest incidence of thyroid carcinomas in the world is among female Chinese residents of Hawaii. In Hawaii, the incidence of FTC ranges from 10-3 new cases a year per million inhabitants.

In recent years, the frequency of FTC has appeared to increase; however, this increase is related to improvement in diagnostic techniques and a successful campaign of information about this carcinoma.^[10]

Of all thyroid cancers, 17-20% are follicular. According to world epidemiologic data, follicular carcinoma is the second most common thyroid neoplasm; in some geographic areas, however, FTC is the most common thyroid tumor. The relative incidence of follicular carcinoma is higher in areas of endemic goiter.

Race-, sex-, and age-related demographics

FTC occurs more frequently in Whites than in Blacks. The incidence is higher in women than men by a factor of 2-3 or more. The female-to-male ratio varies by patient age: it is 4:1 in patients younger than 19 years and older than 45 years, and 3:1 in patients 20-45 years.

In postmenopausal women, a weak positive association (relative risk < 1.20) has been found between increased body mass index and thyroid cancer.^[11]

Thyroid carcinoma occurs in all age groups, but is most oftten diagnosed in persons aged 45–64 years. Median age at diagnosis is 51 years.^[12] In older adults, FTC tends to occur more often than papillary thyroid carcinoma.

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Prognosis

Most FTCs are slow growing and are overall associated with a very favorable prognosis. Mean mortality rates are 1.5% in females and 1.4% in males.  However, FTC prognosis is related to age, sex, and staging. In general, if the cancer does not extend beyond the capsule of the gland, life expectancy is minimally affected. Prognosis is better in female patients and in patients younger than 40 years. The 5-year relative survival rate for 2010-2016 was 98.3%.^[12]

Current World Health Organization classification proposes three subtypes of FTC: minimally invasive, encapsulated angioinvasive, and widely invasive.^[13] O'Neill et al reported that disease‐free survival rates at 40 months in patients with those three subtypes were 97%, 81%, and 46%, respectively.^[14]

For FTC, mean survival rate after 10 years is 85%.^[15] Metastases are still rare and are due to angioinvasion and hematogenous spread. Lymphatic involvement is even more rare, occurring in less than 10% of cases. In some patients, however, metastases are found at diagnosis.^[16]

In a Spanish study of FTC in 66 patients, with follow-up of 99 ± 38 months, disease-related mortality was 3%; disease-free survival rates were 71% at 5 years and 58% at 10 years. The main predictive factors for recurrence were the presence of local clinical symptoms and infiltration into neighboring structures.^[17]

A relatively large prospective study by Sugino et al demonstrates that age and primary tumor size may result in poorer outcome for patients with distant metastases. Authors recommend conservative management for younger patients with minimally invasive follicular thyroid carcinoma with small tumors.^[18]

Unlike medullary thyroid carcinoma, FTC is not part of a multiple endocrine neoplasia (MEN) syndrome.

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History

Many cases of follicular thyroid cancer (FTC) are subclinical. The most common presentation of thyroid cancer is as an asymptomatic thyroid mass or nodule that can be felt in the neck. Pain seldom is an early warning sign of thyroid cancer.

Record a thorough medical history to identify any risk factors or symptoms. For any patient with a lump in the thyroid that has appeared recently, focus on any prior exposure to ionizing radiation, as well as the cumulative lifetime exposure; 1 Gy of radiation to the thyroid has an estimated attributable risk of 88%. For children, doses as low as 50-100 mGy are associated with an increased risk of thyroid cancer, with a linear dose response up to 10-20 Gy. This risk persists for about 4 years from exposure.^[19]  Note that of the thyroid cancers, papillary thyroid carcinoma has the highest risk with ionizing radiation.

Also consider any family history of thyroid cancer.^[20]

Some patients have persistent cough, difficulty breathing, or difficulty swallowing. Other signs and symptoms (eg, pain, stridor, vocal cord paralysis, hemoptysis, rapid enlargement) are rare. Those can be caused by less serious problems.

At diagnosis, 10-15% of patients have distant metastases to bone and lung and initially are evaluated for pulmonary or osteoarticular symptoms (eg, pathologic fracture, spontaneous fracture).

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Physical Examination

Palpate the patient's neck to evaluate the size and firmness of the thyroid and to check for any thyroid nodules. The principal sign of thyroid carcinoma is a firm and nontender nodule in the thyroid area.

Some patients have a tight or full feeling in the neck, hoarseness, or signs of tracheal or esophageal compression.

Palpable thyroid nodules are usually solitary, with a hard consistency, an average size of less than 5 cm, and ill-defined borders. This nodule is fixed in respect to surrounding tissues and moves with the trachea at swallowing.

Usually, signs of hyperthyroidism or hypothyroidism are not observed.

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Approach Considerations

Current guidelines from the National Comprehensive Cancer Network recommend that patients with thyroid nodules undergo measurement of thyroid-stimulating hormone (TSH) and ultrasound of the thyroid and central neck; ultrasound of the lateral neck may be considered. Patients with thyroid nodules and a low TSH level should have radioiodine imaging: if this study reveals an autonomously functioning (“hot”) nodule, the patient should be evaluated for thyrotoxicosis.^[3]

Patients with hypofunctional nodules, and those with a normal or elevated TSH level, should be considered for fine-needle aspiration biopsy (FNAB), based on clinical and sonographic features. A cytologist could experience difficulty in distinguishing some benign cellular adenomas from their malignant counterparts (ie, follicular and Hürthle cell adenomas from carcinomas).^{[21, 22]} On final pathologic assessment, approximately 15-40% of FNAB samples with a cytologic diagnosis of “suspicious for follicular neoplasm” prove to be malignant.^[3]

A prognostic indicator of significant value may be RAS genotyping by polymerase chain reaction (PCR), which may help in the clinical and histologic reassessment of these tumors. In thyroid nodules with otherwise indeterminate cytology, the presence of RAS mutation may potentially alters initial surgical management, as it indicates a markedly elevated increased risk for cancer (∼85%).^[23]

Determining the serum level of carcinoembryonic antigen (CEA) may be helpful; the reference value is less than 3 ng/dL. However, the implications of CEA elevation are not specific because CEA levels are elevated in several cancers, and many healthy people may have small amounts of CEA, especially pregnant women and heavy smokers.

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Imaging Studies

Ultrasonography is the first imaging study that must be performed in any patient with suspected thyroid malignancy.

Ultrasonography is noninvasive and inexpensive, and it represents the most sensitive procedure for identifying thyroid lesions and determining the diameter of a nodule (2-3 mm). Ultrasonography is also useful to localize lesions when a nodule is difficult to palpate or is located deeply.

A study by Xing et al demonstrates that the strain ratio measurement of thyroid lesions, which is a fast standardized method for analyzing stiffness inside examined areas, can be used as an additional tool with B-mode ultrasonography and helps increase the diagnostic performance of the examination.^[24]

Ultrasonography can determine whether a lesion is solid or cystic and can detect the presence of calcifications. The rate of accuracy of ultrasonography in categorizing nodules as solid, cystic, or mixed is near 90%.

Ultrasonography may direct a fine-needle aspiration biopsy (FNAB).

Disadvantages of thyroid ultrasonography are that the test cannot distinguish benign nodules from malignant nodules, and it cannot be used to identify true cystic lesions.

Pulsed and power Doppler ultrasonography may provide important information about the vascular pattern and the velocimetric parameters.^[25] Such information can be useful preoperatively to differentiate malignant from benign thyroid lesions.

Prior to the introduction of FNAB, thyroid scintigraphy (or thyroid scanning) performed with technetium Tc 99m pertechnetate (99mTc) or radioactive iodine (I-131 or I-123) was the initial diagnostic procedure of choice in thyroid evaluation.

Thyroid scanning is not as sensitive or specific as FNAB in distinguishing benign nodules from malignant nodules.

The scintigraphy procedure performed with 99mTc has a high error rate because although 99mTc is trapped in the thyroid, as iodide is, it is not organified there. 99mTc has a short half-life and cannot be used to determine functionality of a thyroid nodule.

Radioactive iodine is trapped and organified in the thyroid and can be used to determine functionality of a thyroid nodule. Iodine-containing compounds and seafood interfere with any tests that use radioactive iodine. Scintigraphic images of the thyroid are acquired 20-40 minutes after IV administration of radionuclide. In more than 90% of cases, clearly benign nodules appear as hot because they are hyperfunctioning and have a high uptake of radionuclide and, physiologically, of iodine. Malignant nodules usually appear as cold nodules because they are not functioning.

Thyroid scanning is helpful and specific in localizing the tumor preoperatively and identifying residual thyroid tissue immediately postoperatively. It also is used to follow-up for tumor recurrence or metastasis. Thyroid scanning could be useful in diagnosing thyroid tumors in patients with benign lesions (by FNAB) or solid lesions (by ultrasonography).

Integrated imaging, using 18F-FDG and coregistered total body PET and CT scan, seems to be effective in improving diagnostic accuracy in patients with iodine-negative differentiated thyroid carcinoma, allowing precise localization of the tumor tissue.^[26] In addition, image fusion by integrated PET/CT offers more information than side-by-side interpretation of single images obtained separately with CT and PET.

Chest radiography, CT scanning, and MRI usually are not used in the initial workup of a thyroid nodule, except in patients with clear metastatic disease at presentation. These tests are second-level diagnostic tools and are useful in preoperative patient assessment.

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Other Tests

Perform indirect or fiberoptic laryngoscopy to evaluate airway and vocal cord mobility and to have preoperative documentation of any unrelated abnormalities.

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Histologic Findings

On gross examination, FTC appears encapsulated and solitary and is often found in necrotic and/or hemorrhagic areas, as depicted in the images below.

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Follicular thyroid carcinoma. Surgical specimen of a large goiter. Total thyroidectomy was performed because of the presence of a solid nodule in the ....

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Follicular thyroid carcinoma. The right lobe of the thyroid was sectioned and reveals a large solid nodule with necrotic and hemorrhagic areas. Histol....

Histologically, the lesion may be encapsulated and may demonstrate well-defined follicles containing colloid, making its distinction from follicular adenoma difficult. Examples of FTC are shown in the images below.

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Follicular thyroid carcinoma. Histologic pattern of a mildly differentiated follicular thyroid carcinoma (250 X). Image courtesy of Professor Pantaleo....

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Follicular thyroid carcinoma. Histologic pattern of a rare lymph node metastasis of follicular thyroid carcinoma (140 X). Image courtesy of Professor ....

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Follicular thyroid carcinoma. Histologic pattern of a rare lymph node metastasis of follicular thyroid carcinoma (250 X). Image courtesy of Professor ....

See the list below:

• Histologic and cellular patterns of endocrine tumors do not allow diagnosis of carcinoma; therefore, this diagnosis is made by finding pseudocapsule and/or blood vessel invasion, not by cellular morphology.
• High magnification of the abortive follicles may demonstrate atypia of the follicular epithelium and intervening stroma.
• Thyrocytes are large and show an abnormal nuclear/cytoplasmic ratio with several mitoses.
• Presence of colloid-rich follicles lined by flattened follicular cells that are occasionally accompanied by several histiocytes is maintained in a benign lesion.
• Definitive diagnosis is often not possible with samples obtained from FNAB because accurate distinction between benign and malignant lesions cannot be made.

Because of the well-known role of the RAS-RAF-MEK-MAP kinase pathway in thyroid carcinogenesis, n-RAS expression may be evaluated to differentiate follicular and papillary cancer of the thyroid.

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Staging

The accurate assessment of the proliferative grade and the extent of invasion have high prognostic value and are mandatory in every specimen.

The staging of well-differentiated thyroid cancers is related to age for the first and second stages but not for the third and fourth stages.

In patients younger than 45 years, staging is as follows:

• Stage I: Any T, any N, M0 (Cancer is in the thyroid only.)
• Stage II: Any T, any N, M1 (Cancer has spread to distant organs.)

In patients older than 45 years, staging is as follows:

• Stage I: T1, N0, M0 (Cancer is in the thyroid only, in one or both lobes.)
• Stage II: T2, N0, M0 and T3, N0, M0 (Cancer is in the thyroid only and is larger than 1.5 cm.)
• Stage III: T4, N0, M0 and any T, N1, M0 (Cancer has spread outside the thyroid but not outside of the neck.)
• Stage IV: Any T, any N, M1 (Cancer has spread to other parts of the body.)

See Thyroid Cancer Staging for more information.

American Thyroid Association staging

The American Thyroid Association (ATA) has published guidelines for estimating risk of recurrence in differentiated thyroid cancer after total thyroidectomy and radioactive iodine remnant ablation. The guidelines provide initial risk estimates and re-stratification based on response to initial therapy.^[27]

For initial risk estimates, patients are considered at low risk if all of the following are present:

• No local or distant metastases
• All macroscopic tumor has been resected
• No invasion of locoregional tissues
• Tumor does not have aggressive histology (eg, tall cell, insular, columnar cell carcinoma, Hürthle cell carcinoma, FTC)
• No vascular invasion
• No iodine-131 (¹³¹I) uptake outside the thyroid bed on the post-treatment scan, if done

Patients are considered at intermediate risk if any of the following is present:

• Microscopic invasion into the perithyroidal soft tissues
• Cervical lymph node metastases or ¹³¹I uptake outside the thyroid bed on the post-treatment scan done after thyroid remnant ablation
• Tumor with aggressive histology or vascular invasion (eg, tall cell, insular, columnar cell carcinoma, Hürthle cell carcinoma, FTC)

Patients are considered at high risk if any of the following is present:

• Macroscopic tumor invasion
• Incomplete tumor resection with gross residual disease
• Distant metastases

The ATA guidelines define response to initial therapy (6–24 months after radioactive iodine ablation) as excellent if all the following are present:

• Suppressed and stimulated thyroglobulin (Tg) < 1 ng/mL
• No evidence of disease on neck ultrasound (US)
• Negative cross-sectional and/or nuclear medicine imaging (if performed)

Response is defined as acceptable if any of the following are present:

• Suppressed Tg < 1 ng/mL and stimulated Tg ≥ 1 and < 10 ng/mL
• Neck US with nonspecific changes or stable sub-centimeter lymph nodes
• Cross-sectional and/or nuclear medicine imaging with nonspecific changes, although not completely normal

Response is defined as incomplete if any of the following are present:

• Suppressed Tg ≥ 1 ng/mL or stimulated Tg ≥ 10 ng/mL
• Rising Tg values
• Persistent or newly identified disease on cross-sectional and/or nuclear medicine imaging

A comparison study in 98 patients with FTC concluded that the ATA staging system predicts recurrence rate and survival better than TNM staging. Hazard ratios were 4.67 with ATA staging versus 1.26 for TNM staging.^[28]

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Thyroid Studies

Perform complete assessment of thyroid function in any patient with thyroid lumps. In addition to TSH, measure thyroxine, triiodothyronine, and serum levels of thyroglobulin, calcium, and calcitonin.

Levels above the reference range of thyroxine (T4; reference range, 4.5-12.5 mcg/dL), triiodothyronine (T3; reference range, 100-200 ng/dL), and TSH (reference range, 0.2-4.7 mIU/dL) may indicate thyroid cancer. Available studies are not specific for FTC.

TSH suppression test

Thyroid cancer is autonomous and does not require TSH for growth, whereas benign thyroid lesions do. Therefore, when exogenous thyroid hormone feeds back to the pituitary to decrease the production of TSH, thyroid nodules that continue to enlarge are likely to be malignant. However, consider that 15-20% of malignant nodules are suppressible.

Preoperatively, the test is useful for patients with nontoxic solitary benign nodules and for women with repeated inconclusive test results. Postoperatively, the test also is useful in follow-up of FTC cases.

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Fine-Needle Aspiration Biopsy

Fine-needle aspiration biopsy (FNAB) is considered the best first-line diagnostic procedure for a thyroid nodule; it is a safe and minimally invasive test. It is the required procedure for the diagnostic evaluation of the classic solitary thyroid nodule.

Local anesthesia is administered at the puncture site, and a 21G or 23G aspiration biopsy needle is guided into the mass. The nodule is held with the fingers of the left hand while a needle is introduced through the skin into the nodule with the right hand.

After aspiration, the material is placed on a glass slide, fixed with alcohol-acetone, and stained according to the technique of Papanicolaou.

Accuracy of FNAB is better than that of any other test for uninodular lesions. Sensitivity of the procedure is near 80%, specificity is near 100%, and errors can be diminished using ultrasound guidance. False-negative and false-positive results occur less than 6% of the time.

A cytologist could experience difficulty in distinguishing some benign cellular adenomas from their malignant counterparts (ie, follicular and Hürthle cell adenomas from carcinomas).

Thyroid biopsy could be performed using the classic Tru-Cut or Vim-Silverman needles, but FNAB is preferable. Patients comply best with FNAB.

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Approach Considerations

The initial treatment for cancer of the thyroid is surgical. The exact nature of the surgical procedure to be performed depends for the most part on the extent of the local disease. A consensus approach might be to perform a total thyroidectomy if the primary tumor is larger than 1 cm in diameter or if there is extrathyroidal involvement or distant metastases. Clinically evident lymphadenopathy should be removed with a neck dissection. If the primary tumor is less than 1 cm in diameter, a unilateral lobectomy might be considered.

Current National Comprehensive Cancer Network (NCCN) guidelines recommend lobectomy plus isthmusectomy as the initial surgery for patients with follicular neoplasms, with prompt completion of thyroidectomy if invasive follicular thyroid carcinoma (FTC) is found on the final histologic section. Therapeutic neck dissection of involved compartments is recommended for clinically apparent/biopsy-proven disease.^[3]

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.^[3]

About 4-6 weeks after surgical thyroid removal, patients must have radioiodine to detect and destroy any metastasis and any residual tissue in the thyroid. Administer therapy until no further radioiodine uptake is noted.

Patients take thyroid replacement therapy (ie, levothyroxine [L-T4]) for life. This entails taking 2.5-3.5 mcg/kg of L-T4 every day. The thyroxine is given in the dose necessary to inhibit thyrotropin to a value of 0.1-0.5 mU/L.

This treatment plan is generally successful. However, a 10-year recurrence rate of 20-30% may be seen in older patients, in patients with primary tumors greater than 4 cm in diameter, and in patients where tumor has spread beyond the thyroid boundaries and where lymph node involvement is widespread. Once metastatic thyroid cancer becomes resistant to radioiodine, the 10-year survival is less than 15%.

A number of indications for external beam radiation therapy (EBRT) apply to the management of FTC. If all gross disease cannot be resected, or if residual disease is not avid for radioactive iodine, EBRT is often employed for locally advanced disease.

Similarly, radiation therapy is indicated for unresectable disease extending into adjacent structures, such as the trachea, esophagus, great vessels, mediastinum, and/or connective tissue. In this situation, radiation therapy doses of 6000-6500 cGy are typically used. Following radiation therapy for unresectable disease, the patient should undergo radioactive iodine (I-131) scanning. If uptake is detected, a dose of I-131 should be administered.

EBRT increases the local-regional control of the residual disease for patients with locally advanced differentiated thyroid carcinoma.^[29] EBRT also may be used after resection of recurrent FTC that is no longer avid for radioactive iodine.

In the postoperative setting, radiation therapy doses of 5000-6000 cGy are commonly delivered to the tumor bed to reduce the risk of local-regional recurrence.

Careful treatment planning (typically with multiple radiation therapy fields) should be employed to minimize the risks of radiation therapy complications.

Finally, a palliative course of radiation therapy is useful to relieve pain from bone metastases.

Chemotherapy with cisplatin or doxorubicin has limited efficacy, producing occasional objective responses (generally for short durations). Because of the high toxicity of cisplatin and doxorubicin, chemotherapy may be considered in symptomatic patients with recurrent or progressive disease. It could improve quality of life in patients with bone metastases. No standard protocol exists for chemotherapy of metastatic FTC.

FTC is a highly vascular lesion. In patients with bone metastases who experience severe pain that does not respond to palliative radiation, arterial embolization of the tumor might be considered.

The possible involvement of angiogenesis in the progression of metastatic thyroid carcinoma has suggested a role for the multikinase inhibitor sunitinib, which may inhibit angiogenesis. A phase II trial in 23 patients with advanced differentiated thyroid cancer who had received at least one course of radioactive iodine treatment demonstrated that sunitinib exhibits significant anti-tumor activity. Of the 23 patients, six (26%) achieved a partial response and 13 (57%) had stable disease.^[30]

See Thyroid Cancer Treatment Protocols for summarized information.

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Surgical Care

Surgery is the definitive management of thyroid cancer, and various types of operations may be performed. 

In a study by Asari et al of 207 patients with FTC, the 127 patients with minimally invasive growth had no lymph node metastases. According to the authors, total thyroidectomy is recommended for all patients with FTC, but patients with widely invasive FTC need more aggressive surgery because of a higher tendency toward lymph node metastases. Patients with minimally invasive disease have an excellent prognosis with a limited need for nodal surgery, according to this study.^[31]

In a study by Spinelli et al of pediatric patients with FTC (age 18 years and younger), total thyroidectomy was performed in 9 of the 30 patients; 21 initially underwent hemithyroidectomy, but 11 of those subsequently required completion of thyroidectomy.^[32]  The authors conclude that a conservative approach to surgery seems valid for pediatric patients diagnosed with minimally invasive FTC; they recommend completion of thyroidectomy for patients with wide vascular invasion and/or a tumor > 4 cm, especially with a high postoperative thyroglobulin level, and advise that total thyroidectomy followed by radioiodine therapy is generally indicated for patients with one or more of the following:

• Multifocal neoplasia
• Tumor size ≥4 cm
• Extrathyroid extension
• Lymph node metastasis
• Distant metastasis

Lobectomy with isthmectomy

This represents the minimal operation for a potentially malignant thyroid nodule.

A study of 889 thyroid cancer patients who underwent either total thyroidectomy or thyroid lobectomy showed similarly high rates of survival among both groups.^[33] Patients younger than 40 years who have FTC nodules that are less than 1 cm in size, well defined, minimally invasive, and isolated may be treated with hemithyroidectomy and isthmectomy.

Subtotal thyroidectomy (near-total thyroidectomy)

Subtotal thyroidectomy is preferable if it is feasible, as it carries a lower incidence of complications (eg, hypoparathyroidism, superior and/or recurrent laryngeal nerve injury).

Moreover, total thyroidectomy does not improve the long-term prognosis.

Total thyroidectomy (removal of all thyroid tissue, with preservation of the contralateral parathyroid glands)

Approximately 10% of patients who have had total thyroidectomy demonstrate cancer in the contralateral lobe. Therefore, residual thyroid tissue has the potential to dedifferentiate to anaplastic cancer.

Perform total thyroidectomy in patients with FTC who are older than 40 years and in any patient with bilateral disease; furthermore, recommend total thyroidectomy to anyone with a thyroid nodule and a history of irradiation.

Some studies show lower recurrence rates and increased survival rates in patients who have undergone total thyroidectomy. This surgical procedure also facilitates earlier detection and treatment of recurrent or metastatic carcinoma. This surgical option is mandatory in patients with FTC ascertained by postoperative histologic studies (ie, if a very well-differentiated tumor is discovered) after a one-side lobectomy, with or without isthmectomy.

When the primary tumor has spread outside the thyroid and involves adjacent vital organs, such as the larynx, trachea, or esophagus, preserve these organs at the first surgical approach. However, the surrounding soft tissues, including muscles and involved areas of the trachea and/or esophagus, may be sacrificed whenever they are involved directly in the differentiated thyroid carcinoma and their local resection is easily feasible. Surgical resection of one or more brain metastases may prolong survival from 4 to 22 months.

Minimally invasive techniques

A number of minimally invasive approaches have been develpoed for the treatment of thyroid carcinoma, including minimally invasive video-assisted thyroidectomy (MIVAT), transaxillary endoscopic thyroidectomy, and robotic thyroidectomy.^[34]

Robotic-assisted thyroidectomy

A study by Lee et al found that the application of robot technology to endoscopic thyroidectomy may overcome the limitations of conventional surgery.^[35] A systematic review and meta-analysis by Jackson et al of robotic thyroidectomy via a gasless, axillary approach found that operative time was longer with robotic than conventional thyroidectomy, but with a trend to be shorter than with endoscopic approaches. Risks of robotic surgery were similar to those of open and endoscopic approaches. Compared with patients undergoing conventional thyroidectomy, patients who underwent robotic surgery reported greater cosmetic satisfaction.^[36]

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Targeted Therapy

A growing number of targeted agents are available for the treatment of recurrent follicular thyroid cancer.^[37] Tyrosine kinase inhibitors (TKIs) that are approved for radioiodine-refractory differentiated thyroid cancer include the following:

• Sorafenib^[38]
• Lenvatinib^[39]
• Cabozantinib^[40]

The following agents are approved for treatment of advanced or metastatic radioiodine-refractory cases that are positive for RET (rearranged during transfection) mutations:

• Selpercatinib^[41]
• Pralsetinib^[42]

The following are tumor-agnostic agents approved for treatment of solid tumors, including thyroid cancer, with NTRK mutations:

• Larotrectinib^[43]
• Entrectinib^[44]

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Consultations

Schedule elderly patients for cardiologic assessment because of the high risk of subclinical hypothyroidism episodes.

Consult an otolaryngologist, especially in patients with thyroid disease who have voice disturbances.

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Complications

If it is neglected, FTC may produce symptoms due to the compression and/or infiltration of the surrounding tissues, and it may metastasize to lung and bone.

Surgical treatment of FTC may cause complications, partially because of the variable anatomy of the neck. Complication rates, especially with total thyroidectomy, are lower in the hands of experienced surgeons.^[45]  Possible complications include the following:

• Hypothyroidism^[46]
• Dysphagia due to damage of the upper laryngeal nerve
• Vocal cord paralysis due to damage of the recurrent laryngeal nerve
• Hypoparathyroidism due to parathyroid gland ablation.

Radioiodine administration may have the following consequences:

• Radiation thyroiditis and transient thyrotoxicosis in patients who have undergone simple lobectomy
• Sialoadenitis, because radioiodine is taken up by the salivary glands
• Nausea, anorexia, and headache (uncommon)
• Pulmonary fibrosis in patients with large lung metastases
• Brain edema in patients with brain metastases (this may be prevented by glucocorticoid treatment)
• Permanent sterility and transient oligospermia or menstrual irregularities
• Teratogenesis and spontaneous abortions
• A slight increase in the risk of leukemias or breast and bladder carcinomas.

In a study of 438 patients with thyroid cancer, similar outcomes were achieved with low-dose radioiodine plus thyrotropin alfa treatment and high-dose radioiodine treatment, and low-dose treatment was associated with a lower rate of adverse events.^[47]

The most frequent sites of metastasis are lung and bone, followed by the brain and the liver; metastasis to other sites occurs less frequently. Metastatic potential seems to be a function of primary tumor size; however, metastases without thyroid pathology identified on physical examination may be found in patients with microscopic FTC.

• References

Long-Term Monitoring

Perform postoperative scintiscan of the neck after 4-6 weeks without thyroid hormone replacement. At this time, a scan of the neck demonstrates whether thyroid tissue is still present. If thyroid tissue is present, a dose of radioactive iodine is administered to destroy residual tissue. The patient is then placed on lifelong thyroid replacement with L-T4. Repeat the scintiscan 6-12 months after ablation and, thereafter, every 2 years. Prior to the scan, L-T4 must be withdrawn for approximately 4-6 weeks to maximize thyrotropin stimulation of any remaining thyroid tissue.

Radioactive iodine may ablate the metastatic tissue in the lungs and bone. In fact, metastases of FTC appear to be more amenable to radioiodine therapy than metastases of papillary carcinoma.

For a single CNS metastasis, consider neurosurgical resection and radioiodine treatment, perhaps combined with recombinant human thyroid-stimulating hormon (rhTSH) and steroids, and/or radiation therapy.

Evaluate thyroglobulin serum levels every 6-12 months for at least 5 years. Consider a level higher than 20 ng/mL, after TSH suppression, to be abnormal. A recurrence of thyroid cancer can be detected if a rise in the thyroglobulin level is found on monitoring. All patients who have undergone total thyroidectomy and those who have had radioactive ablation of any remaining thyroid tissue should be treated with thyroid hormone suppression. Individualize the degree of suppression to avoid complications such as subclinical hyperthyroidism.

A study by Brassard et al found that thyroglobulin measurements allow prediction of long-term recurrence with excellent specificity. TSH stimulation may be avoided when thyroglobulin levels measured 3 months after ablation are less than 0.27 ng/mL during levothyroxine treatment.^[48]

A patient who has had a thyroidectomy without parathyroid preservation will require lifelong vitamin D and calcium supplementation.

More specific treatment information for FTC can be found at the National Comprehensive Cancer Network website, in the NCCN Clinical Practice Guidelines in Oncology section.

The American Thyroid Association Taskforce on Radioiodine Safety released recommendations to help guide physicians and patients in safe practices after treatment, including reminders in the form of a checklist.^[49]

• References

Guidelines Summary

Guidelines Contributor: Kemp M Anderson Medical University of South Carolina College of Medicine

The following organizations have released guidelines for the diagnosis and/or management of thyroid cancer:

• American Thyroid Association (ATA)^[50]
• National Comprehensive Cancer Network (NCCN)^[3]
• European Society for Medical Oncology (ESMO)^[51]
• American Association of Clinical Endocrinologists/Associazione Medici Endocrinologi/European Thyroid Association (AACE/AME/ETA^[52]  (diagnosis only)

Diagnosis

All the guidelines advocate ultrasound 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.^{[3, 53, 51]}

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^{[50, 3, 52]} :

• >0.5 cm in diameter (ATA)^[50]
• >1 cm in diameter (ESMO)^[51]
• ≥1 cm for high ultrasound risk thyroid lesions; >2 cm for intermediate ultrasound risk lesions or low ultrasound risk only when increasing in size or associated with a risk history (AACE/AME/ETA)^[52]
• >1 cm if suspicious sonographic features are present;  ≥1.5 cm for moderately suspicious nodules and ≥2.5 cm for mildly suspicious nodules. (NCCN)^[3]

NCCN and AACE/AME/ETA recommend radionuclide imaging in patients with a low TSH level.^{[50, 3, 52]}

Differentiated thyroid cancers arise from thyroid follicular epithelial cells and constitute 90% of all thyroid cancers. The subtypes and approximate frequencies of differentiated thyroid cancers are as follows:

• Papillary – 85%
• Follicular – 10%
• Hürthle or oxyphil – 5%

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 ultrasound (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.^[50]  

Papillary thyroid cancer is characterized by the following US features:

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

Follicular thyroid cancer is characterized by the following US features:

• Iso- to hyper-echoic
• Thick irregular halo

Benign US features are as follows:

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

In 2017, an ATA task force recommended that encapsulated follicular variant papillary thyroid carcinoma (eFVPTC) without capsular or vascular invasion be reclassified as noninvasive follicular thyroid neoplasm with papillary-like nuclear features (NIFTP), given its excellent prognosis. This was a weak recommendation based on moderate-quality evidence.^[54]

The 2019 ESMO guidelines recommend pathological diagnosis of all thyroid tumors be made according to the 2017 WHO classification.^[51]

Malignancy risk

Cytological 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 comprises the following categories and ranges of estimated risk of malignancy^[55] :

• Malignant (risk 97-100%)
• Suspicious for malignancy (risk 67-83%)
• Follicular neoplasm (risk 23-34%)
• Atypia of undetermined significance or follicular lesion of undetermined significance (nuclear atypia, risk 36-44%; other, risk 15-23%)
• Benign (risk 2-7%)
• Nondiagnostic (risk 5-20%)

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.^[50]

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.^[50] 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.^[50]

The NCCN recommends FNAB as 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)^[3] :

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

• References

Treatment

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.^[50]

The ATA recommends that if cytology readings report a follicular neoplasm, an ¹²³I thyroid scan may be considered, especially if serum thyroid-stimulating hormone (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.^[50]

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.^[3]

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.^[3]

While ESMO guidelines consider thyroidectomy to be standard of care for other thyroid tumors, they recommend proposing active ultrasound surveillance of every 6–12 months for unifocal papillary microcarcinomas (≤10 mm) with no evidence of extracapsular extension or lymph node metastases. Lobectomy (instead of total thyroidectomy) may be proposed for selected low-risk (T1a–T1b–T2, N0) tumors.^[51]

Radioiodine Therapy

NCCN guidelines recommend radioiodine (¹³¹I) therapy if any of the following are present^[3] :

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

Radioiodine therapy is not recommended if all of the following are present^[3] :

• Classic papillary thyroid carcinoma (PTC)
• 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 are present when the combination of clinical factors predicts a significant risk of recurrence:^[3]

• 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 are present:^[50]

• 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 < 1 cm without other higher- risk features; or for patients with multifocal cancer when all foci are < 1 cm in the absence of other higher-risk features.^[50]

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.^[50]

The ATA and NCCN guidelines recommend treatment with levothyroxine to suppress thyroid-stimulating hormone (TSH) levels. Degree of suppression is based on risk, as follows ^{[50, 3]} :

• Low-risk patients - Maintenance of the TSH at or slightly below the lower limit of normal (0.1 to 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

• References

Medication Summary

The most useful drugs for postsurgical treatment of follicular thyroid cancer (FTC) are L-thyroxine (L-T4) and radioiodine. Antineoplastic drugs such as cisplatin and doxorubicin may be useful for palliation in patients with metastases. Targeted therapy may be given for cases refractory to radioiodine.

• References

L-T4, L-thyroxine, levothyroxine (Synthroid)

• Dosing, Interactions, etc.

Clinical Context:  Useful for prevention of hypothyroidism and to stop TSH stimulation. In active form, influences growth and maturation of tissues. Involved in normal growth, metabolism, and development.

• References

Class Summary

These agents treat thyroid hormone deficiency.

• References

Sodium iodide I-131 (Hicon)

• Dosing, Interactions, etc.

Clinical Context:  Radioiodine is taken up by thyroid tissue and cannot be used in metabolic pathways. Emits beta and gamma radiation that causes destruction of thyroid tissue along a diameter of 400-2000 mcm. Results in destruction of all residual thyroid tissues, either pathologic or normal.

• References

Class Summary

These agents reduce serum thyroid hormone levels.

• References

Cisplatin (Platinol)

• Dosing, Interactions, etc.

Clinical Context:  May be helpful in palliating symptoms in patients with progressive disease. Like other antiproliferative drugs, dosage related to body surface area.

• References

Doxorubicin (Adriamycin)

• Dosing, Interactions, etc.

Clinical Context:  As reported for cisplatin, may be helpful in palliating symptoms in patients with progressive disease. Dosage related to body surface area.

• References

Sorafenib (Nexavar)

• Dosing, Interactions, etc.

Clinical Context:  Multikinase inhibitor (including VEGF and PDGF receptor kinases), reduces tumor cell proliferation in vitro, may act at least partially by inhibiting tumor angiogenesis. Indicated for locally recurrent or metastatic, progressive, differentiated thyroid cancer (DTC) that is refractory to radioactive iodine treatment

• References

Lenvatinib (Lenvima)

• Dosing, Interactions, etc.

Clinical Context:  Receptor tyrosine kinase inhibitor that inhibits the kinase activities of vascular endothelial growth factor (VEGF) receptors VEGFR1 (FLT1), VEGFR2 (KDR), and VEGFR3 (FLT4). Indicated for treatment of locally recurrent or metastatic, progressive, radioactive iodine-refractory differentiated thyroid cancer (DTC)

• References

Cabozantinib (Cabometyx, Cometriq)

• Dosing, Interactions, etc.

Clinical Context:  Tyrosine kinase inhibitor that targets RET, MET, VEGFR-1, -2, and -3, KIT, TrkB, FLT-3, AXL, and TIE-2 pathways; these tyrosine kinases are involved in both normal cellular function and pathologic processes (eg, oncogenesis, metastasis, tumor angiogenesis, and maintenance of tumor microenvironment). Indicated for locally advanced or metastatic differentiated thyroid cancer (DTC) in adults who have progressed following prior VEGFR-targeted therapy and who are radioactive iodine-refractory or ineligible.

• References

Selpercatinib (Retevmo)

• Dosing, Interactions, etc.

Clinical Context:  Kinase inhibitor of wild-type RET (rearranged during transfection) and multiple mutated RET isoforms, as well as vascular endothelial growth factor receptors (VEGFR1, VEGFR3). Indicated for advanced or metastatic RET fusion-positive thyroid cancer in patients who require systemic therapy and whose disease is radioactive iodine-refractory or who are not candidates for radioiodine.

• References

Pralsetinib (Gavreto)

• Dosing, Interactions, etc.

Clinical Context:  Selective inhibitor of RET alterations and resistant mutations; specifically designed to spare VEGFR2 and other kinases with the potential to drive off-target toxicityIndicated for advanced or metastatic RET-fusion positive thyroid cancer in adults who require systemic therapy and whose disease is radioactive iodine-refractory or who are not candidates for radioiodine therapy.

• References

Larotrectinib (Vitrakvi)

• Dosing, Interactions, etc.

Clinical Context:  Inhibitor of tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC. Indicated for adult and pediatric patients with solid tumors that have a neurotrophic tyrosine receptor kinase (NTRK) gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and have no alternative treatments or have progressed following treatment.

• References

Entrectinib (Rozlytrek)

• Dosing, Interactions, etc.

Clinical Context:  Inhibitor of c-ros proto-oncogene 1 (ROS1), anaplastic lymphoma kinase (ALK), and tropomyosin receptor tyrosine kinases (TRKs) TRKA, TRKB, and TRKC; also inhibits JAK2 and TNK2. Indicated for patients with solid tumors that have an NTRK gene fusion without a known acquired resistance mutation, are metastatic or where surgical resection is likely to result in severe morbidity, and progressed following treatment or have no satisfactory alternative therapy

• References

Class Summary

These agents inhibit cell growth and proliferation.

• References