Follicular Thyroid Carcinoma

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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.

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 cytological examination of a needle biopsy specimen may be difficult.

For this 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 should be considered a variant of FTC.

Despite its well-differentiated characteristics, FTC may be overtly or minimally invasive. 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

Life expectancy of affected patients is related to their age; the prognosis is better for younger patients than for patients who are older than 45 years. Patients with FTC are more likely to develop lung and bone metastases than are patients with papillary thyroid cancer. The bone metastases in FTC are osteolytic. Older patients have an increased risk of developing bone and lung metastases.

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. 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.[1]

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.

Pathophysiology

Activating point mutations in the ras oncogene are well known in patients with follicular adenoma and carcinoma,[3, 4, 5] especially in poorly differentiated (55%) and anaplastic carcinoma (52%).

As a result of such mutations, p21-RAS becomes locked in its active conformation, leading to the constitutive activation of the protein and tumor development.[6] The biochemical pathways that this process follows may be therapeutic targets for FTC.[7]

Accidental (not diagnostic) x-ray exposure may influence both occurrence and pattern of ras mutation.

A study of differential gene expression profiling of aggressive and nonaggressive follicular carcinomas identified 94 genes that distinguish follicular carcinomas from follicular adenomas (including PBP and CKS2) and 4 genes that distinguish aggressive follicular carcinomas from nonaggressive follicular carcinomas (NID2, TM7SF2, TRIM2, and GLTSCR2).[8]

Epidemiology

Frequency

United States

The American Cancer Society (ACS) estimates that 53,990 new thyroid cancers will occur in 2018, 13,090 in men and 40,900 in women; the ACS estimates 2060 deaths from thyroid cancer in 2018, 960 in men and 1100 in women. In women, thyroid cancer is the fifth most common cancer, accounting for approximately 5% of all new cases.[9] In the United States, about 10-15% of all thyroid cancers are follicular.

International

Thyroid cancers are quite rare, accounting for only 1.5% of all cancers in adults and 3% in children. The highest incidence of thyroid carcinomas in the world is among female Chinese residents of Hawaii. In Hawaii, the incidence of FTC ranges from 10-30 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.

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.

Mortality/Morbidity

In contrast to other cancers, thyroid cancer is almost always curable. In fact, most FTCs are slow growing and are associated with a very favorable prognosis. Mean mortality rates are 1.5% in females and 1.4% in males.

Mean survival rate after 10 years is 60%. Metastases are still rare and are due to angioinvasion and hematogenous spread. Lymphatic involvement is even more rare, occurring in fewer than 10% of cases. In some patients, metastases are found at diagnosis.

Autopsy reviews show a high incidence of microscopic foci of thyroid carcinoma worldwide.

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

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 ratio varies by patient age:

In postmenopausal women, a weak positive association (relative risk < 1.20) has been found between increased body mass index and thyroid cancer.[10]

Thyroid carcinoma is common in all age groups, with an age range of 15-84 years (mean age, 49 years). In older adults, FTC tends to occur more frequently than papillary carcinoma.

History

Many cases of follicular thyroid cancer (FTC) are subclinical. The most common presentation of thyroid cancer is 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 obtaining history regarding every prior exposure to ionizing radiation, as well as the cumulative lifetime exposure. Consider family history of thyroid cancer.[11]

Some patients have persistent cough, difficulty breathing, or difficulty swallowing. Other symptoms (eg, pain, stridor, vocal cord paralysis, hemoptysis, rapid enlargement) are rare. These symptoms 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).

Physical

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. This mass is painless.

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.

Causes

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.[12, 13]

Therapeutic irradiation of body areas 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, from the 1920s to the 1960s. About 10% of these individuals who were treated with irradiation developed thyroid cancer after a latency period of 30 years.

Patients who need 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.

Incidence of FTC has decreased in geographic areas of endemic goiter after iodized salt was introduced.

Some studies demonstrate that mutations of the ras oncogene could be implicated in the neoplastic transformation of thyrocytes in FTC. n-ras and h-ras mutations (in codon 61) should be the first events in the pathogenesis of FTC, followed by several further mutations (ie, deletions on chromosomes 3q, 11, and 13q).

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

More recently, a histochemical study has shown that delta Np73 plays a role predominantly in the early phase of thyroid carcinoma progression.[14] As a consequence, this seems to be a new effective marker to differentiate follicular adenomas and carcinomas of the thyroid.

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.[1]

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). On final pathologic assessment, only about 20% of patients with an FNAB cytologic diagnosis of “suspicious for follicular neoplasm” will prove to have a follicular thyroid carcinoma.[1]

A prognostic indicator of significant value may be ras genotyping by polymerase chain reaction (PCR) technique, which may help in the clinical and histologic reassessment of these tumors.

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.

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.[15]

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.[16] 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 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.[17] 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.

Other Tests

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

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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Surgical specimen of a large goiter. Total thyroidectomy was performed because of the presence of a solid nodule in the right lobe (note the size of t....



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The right lobe of the thyroid was sectioned and reveals a large solid nodule with necrotic and hemorrhagic areas. Histologic diagnosis is follicular t....

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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Histologic pattern of a mildly differentiated follicular thyroid carcinoma (250 X). Image courtesy of Professor Pantaleo Bufo at University of Foggia,....



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Histologic pattern of a rare lymph node metastasis of follicular thyroid carcinoma (140 X). Image courtesy of Professor Pantaleo Bufo at University of....



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Histologic pattern of a rare lymph node metastasis of follicular thyroid carcinoma (250 X). Image courtesy of Professor Pantaleo Bufo at University of....

See the list below:

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.

Staging

The accurate assessment of the proliferative grading 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 related for the third and fourth stages.

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

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

See Thyroid Cancer Staging for more information.

A comparison study in 98 patients with follicular thyroid carcinoma concluded that the American Thyroid Association (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.[18]

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.

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 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.

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.[1]

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.[1]

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, L-thyroxine [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.[19] 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.[20]

See Thyroid Cancer Treatment Protocols for summarized information.

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.[2]

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 initialiy underwent hemithyroidectomy, but 11 of those subsequently required completion of thyroidectomy.[78]  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:

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.[21] 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, since 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 who are older than 40 years with FTC 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

During the last decade, a number of minimally invasive endoscopic approaches have been proposed for the treatment of thyroid carcinoma, but these techniques may be applied only to a small number of cases—those classified as 'low risk' carcinomas according to the AGES and AMES classifications.

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.[22]

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.

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:

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.[1, 5, 6]

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[23, 1, 24] :

AACE/AME/ETA and NCCN suggest a serum calcitonin assay as an optional test, [23, 24]  but the ATA guidelines make no recommendation on the routine measurement of serum calcitonin because of insufficient evidence. [23]  All three guidelines recommend radionuclide imaging in patients with a low TSH level.[23, 1, 24]

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:

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.[23]  

Papillary thyroid cancer is characterized by the following US features:

Follicular thyroid cancer is characterized by the following US features:

Benign US features are as follows:

Malignancy risk

Cytological analysis of FNAB specimens is used to estimate malignancy risk. The most appropriate cytological classification of malignancy risk is the Bethesda system for thyroid cytopathology, which comprises the following categories[25] :

For cytology “diagnostic of” or “suspicious for” papillary thyroid cancer, surgery is recommended.[23]

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.[23]

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[23] . 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.[23]

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)[23] :

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.[23]

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 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.[23]

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.[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.[1]

Radioiodine Therapy

NCCN guidelines recommend radioiodine (131I) therapy if any of the following are present[1] :

Radioiodine therapy is not recommended if all of the following are present[1] :

Radioiodine therapy is selectively recommended if any of the following are present when the combination of clinical factors predicts a significant risk of recurrence:[1]

The ATA recommends radioiodine therapy for all patients if any of the following are present:[23]

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.[23]

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.[23]

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 [23, 1] :

Medication Summary

The most useful drugs for postsurgical treatment of FTC are L-thyroxine (L-T4) and radioiodine. Antineoplastic drugs such as cisplatin and doxorubicin may be useful for palliation in patients with metastases.

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

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.

Class Summary

These agents treat thyroid hormone deficiency.

Iodine 131, Radioiodine (131-I) (Sodium iodine 131)

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.

Class Summary

These agents reduce serum thyroid hormone levels.

Cisplatin (Platinol)

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

Doxorubicin (Adriamycin)

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

Class Summary

These agents inhibit cell growth and proliferation.

Further Outpatient Care

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 associated with 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.[26]

A patient who has had a thyroidectomy without parathyroid preservation will require vitamin D and calcium for the rest of his or her life.

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.[27]

Further Inpatient Care

In patients with FTC, systematic psychotherapeutic intervention may be very helpful.

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.[28] Possible complications include the following:

Radioiodine administration may have the following consequences:

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.[30]

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.

Prognosis

FTC prognosis is related to age, sex, and staging. In general, if cancer is not extending beyond the capsule of the gland, life expectancy is affected minimally. Prognosis is better in female patients and in patients younger than 40 years. Survival rate is at least 95% with appropriate treatments.

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.[31]

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.[32]

Patient Education

For patient education information, see the Thyroid and Metabolism Center, as well as Thyroid Problems. Patient education information on thyroid cancer is also available on the American Cancer Society Web site.

What is follicular thyroid carcinoma (FTC)?What is the pathophysiology of follicular thyroid carcinoma (FTC)?What is the prevalence of follicular thyroid carcinoma (FTC) in the US?What is the global prevalence of follicular thyroid carcinoma (FTC)?What are the mortality rates of follicular thyroid cancer (FTC)?Which patient groups have the highest prevalence of follicular thyroid cancer (FTC)?Which clinical history findings are characteristic of follicular thyroid carcinoma (FTC)?Which physical findings are characteristic of follicular thyroid carcinoma (FTC)?What causes follicular thyroid carcinoma (FTC)?What are the differential diagnoses for Follicular Thyroid Carcinoma?What is the role of lab testing in the workup of follicular thyroid carcinoma (FTC)?What is the role of imaging studies in the workup of follicular thyroid carcinoma (FTC)?What is the role of laryngoscopy in the workup of follicular thyroid carcinoma (FTC)?Which histologic findings are characteristic of follicular thyroid carcinoma (FTC)?How is follicular thyroid cancer (FTC) staged?How is thyroid function assessed in the workup of follicular thyroid carcinoma (FTC)?What is the role of TSH suppression testing in the workup of follicular thyroid carcinoma (FTC)?What is the role of biopsy in the workup of follicular thyroid carcinoma (FTC)?How is follicular thyroid carcinoma (FTC) treated?What is the role of surgery in the treatment of follicular thyroid carcinoma (FTC)?What is the role of lobectomy in the treatment of follicular thyroid carcinoma (FTC)?What is the role of subtotal (near-total) thyroidectomy in the treatment of follicular thyroid carcinoma (FTC)?What is the role of total thyroidectomy in the treatment of follicular thyroid carcinoma (FTC)?What is the role of minimally invasive surgery in the treatment of follicular thyroid carcinoma (FTC)?What is the role of robotic-assisted thyroidectomy in the treatment of follicular thyroid carcinoma (FTC)?Which specialist consultations are beneficial to patients with follicular thyroid carcinoma (FTC)?Which organizations have issued guidelines on the diagnosis and treatment of follicular thyroid carcinoma (FTC)?What are the guidelines on the diagnosis of follicular thyroid carcinoma (FTC)?What are the ATA guidelines on the treatment of follicular thyroid carcinoma (FTC)?What are the NCCN guidelines on the treatment of follicular thyroid carcinoma (FTC)?What are the NCCN and ATA guidelines on radioiodine therapy for follicular thyroid carcinoma (FTC)?What is the role of medications in the treatment of follicular thyroid carcinoma (FTC)?Which medications in the drug class Antineoplastic Drugs are used in the treatment of Follicular Thyroid Carcinoma?Which medications in the drug class Antithyroid Drug are used in the treatment of Follicular Thyroid Carcinoma?Which medications in the drug class Thyroid Products are used in the treatment of Follicular Thyroid Carcinoma?What is included in the long-term monitoring of follicular thyroid carcinoma (FTC)?What are the possible complications of follicular thyroid carcinoma (FTC)?What is the prognosis of follicular thyroid carcinoma (FTC)?

Author

Luigi Santacroce, MD, Assistant Professor, Medical School, State University at Bari, Italy

Disclosure: Nothing to disclose.

Coauthor(s)

Lodovico Balducci, MD, Professor, Oncology Fellowship Director, Department of Internal Medicine, Division of Adult Oncology, H Lee Moffitt Cancer Center and Research Institute, University of South Florida Morsani College of Medicine

Disclosure: Nothing to disclose.

Specialty Editors

Francisco Talavera, PharmD, PhD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Benjamin Movsas, MD,

Disclosure: Nothing to disclose.

Chief Editor

Neetu Radhakrishnan, MD, Associate Professor (Adjunct) of Medicine, Division of Hematology/Oncology, University of Cincinnati Medical Center; Hematology/Oncology Medical Director, West Chester Outpatient Clinics

Disclosure: Nothing to disclose.

Additional Contributors

Philip Schulman, MD, Chief, Medical Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center

Disclosure: Nothing to disclose.

Acknowledgements

Silvia Gagliardi, MD Consulting Staff, Department of Surgery, Medical Center Vita, Italy

Disclosure: Nothing to disclose.

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Surgical specimen of a large goiter. Total thyroidectomy was performed because of the presence of a solid nodule in the right lobe (note the size of the thyroid lobe at left of the screen).

The right lobe of the thyroid was sectioned and reveals a large solid nodule with necrotic and hemorrhagic areas. Histologic diagnosis is follicular thyroid carcinoma.

Histologic pattern of a mildly differentiated follicular thyroid carcinoma (250 X). Image courtesy of Professor Pantaleo Bufo at University of Foggia, Italy.

Histologic pattern of a rare lymph node metastasis of follicular thyroid carcinoma (140 X). Image courtesy of Professor Pantaleo Bufo at University of Foggia, Italy.

Histologic pattern of a rare lymph node metastasis of follicular thyroid carcinoma (250 X). Image courtesy of Professor Pantaleo Bufo at University of Foggia, Italy.

Surgical specimen of a large goiter. Total thyroidectomy was performed because of the presence of a solid nodule in the right lobe (note the size of the thyroid lobe at left of the screen).

The right lobe of the thyroid was sectioned and reveals a large solid nodule with necrotic and hemorrhagic areas. Histologic diagnosis is follicular thyroid carcinoma.

Histologic pattern of a mildly differentiated follicular thyroid carcinoma (250 X). Image courtesy of Professor Pantaleo Bufo at University of Foggia, Italy.

Histologic pattern of a rare lymph node metastasis of follicular thyroid carcinoma (140 X). Image courtesy of Professor Pantaleo Bufo at University of Foggia, Italy.

Histologic pattern of a rare lymph node metastasis of follicular thyroid carcinoma (250 X). Image courtesy of Professor Pantaleo Bufo at University of Foggia, Italy.