eMedicine Specialties > Oncology > Carcinomas of Endocrine Organs

Thyroid, Follicular Carcinoma

Luigi Santacroce, MD, Assistant Professor, Medical School, State University at Bari, Italy
Silvia Gagliardi, MD, Consulting Staff, Department of Surgery, Medical Center Vita, Italy; Lodovico Balducci, MD, Professor of Oncology and Medicine, University of South Florida College of Medicine; Division Chief, Senior Adult Oncology Program, H Lee Moffitt Cancer Center and Research Institute

Updated: Sep 25, 2009

Introduction

Background

Cancer of the thyroid is the most common endocrine malignancy. Some 5-10% of patients with thyroid cancer will die of their disease. Thyroid neoplasms arising from follicular cells (adenoma, carcinoma, and follicular/papillary carcinoma) show a broad range of overlapping clinical and cytologic features. 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 follicular thyroid cancer. Pathological examination showing capsular or vascular invasion may be required for this determination.

Follicular thyroid carcinoma (FTC) is a well-differentiated tumor. In fact, FTC resembles the normal microscopic pattern of the thyroid. FTC originates in follicular cells and 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.

Papillary/follicular carcinoma must be considered a variant of papillary thyroid carcinoma (mixed form), and Hurthle cell carcinoma should be considered a variant of FTC.

Thyroid cancers are found more often in patients with a history of low-dose or high-dose external irradiation to the cervical or thyroid area. The most common thyroid tumor to develop after exposure to radiation is papillary thyroid cancer. Patients whose thyroid cancer has developed following radiation to the head and neck area may present with more extensive disease. Overall, about 5% of patients with thyroid cancer have metastases beyond the cervical or mediastinal area on initial presentation, 2-3% of patients with papillary thyroid cancer and 11% of patients with follicular thyroid cancer.

Despite its well-differentiated characteristics, follicular carcinoma may be overtly or minimally invasive. In fact, FTC tumors may spread easily to other organs. 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. 

In a recent 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. For patients with minimally invasive disease, patients according to this study have an excellent prognosis with a limited need for nodal surgery.¹

Pathophysiology

Activating point mutations in the ras oncogene are well known in patients with follicular adenoma and carcinoma,^2,3,4 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.⁵ The biochemical pathways that this process follows may be therapeutic targets for FTC.⁶

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

Frequency

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, incidence of FTC ranges from 10-30 new cases a year per million inhabitants. During the last few 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. 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

FTC occurs more frequently in whites than in blacks.

Sex

Incidence is higher in women than men by a factor of 2-3 or more. The ratio varies by patient age:

• In patients younger than 19 years, the female-to-male ratio is 4:1.
• In patients aged 20-45 years, the female-to-male ratio is 3:1.
• In patients older than 45 years, the female-to-male ratio is 4:1.
• In postmenopausal women, a weak positive association (relative risk <1.20) has been found between increased body mass index and thyroid cancer.⁷ A useful and updated source for information about the epidemiology of the Follicular Carcinoma of the Thyroid is the American Cancer Society (ACS) website. 
  
  Estimated New  Thyroid Carcinoma Cases and Deaths by Sex, US, 2008 according to the ACS Cancer Facts and Figures 2008

  Cases and Deaths	Total	Males	Females
  Estimated New Cases	37,340	8,930	28,410
  Estimated Deaths	1,590	680	910

Age

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.

Clinical

History

• Many cases of FTC are subclinical.
• The most common presentation of thyroid cancer is an asymptomatic thyroid mass, or a nodule, that can be felt in the neck.
• 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.⁸
• Some patients have persistent cough, difficulty breathing, or difficulty swallowing.
• Pain seldom is an early warning sign of thyroid cancer.
• 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.^9,10
  • 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.¹¹ As a consequence, this seems to be a new effective marker to differentiate follicular adenomas and carcinomas of the thyroid.

Differential Diagnoses

Other Problems to Be Considered

Metastatic cancer
Leukemias

Workup

Laboratory Studies

• Thyroid function: Perform complete assessment of thyroid function in any patient with thyroid lumps. Available studies are not specific for FTC.
  • 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.
  • Evaluate serum levels of thyroglobulin, calcium, and calcitonin.
  • Determining 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.
• 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.
• A prognostic indicator of significant value may be ras genotyping  by PCR technique, which may help in the clinical and histologic reassessment of these tumors.

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.
  • 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.¹² 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.¹³ 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.

Procedures

• 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.

Histologic Findings

On gross examination, FTC appears encapsulated and solitary and is often found in necrotic and/or hemorrhagic areas (see Images 1-2).

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).

This is the same specimen shown in Image 1. 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.

• 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.

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.

• Younger than 45 years
  • 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.)
• Older than 45 years
  • Stage I: T1, N0, M0 (Cancer is in the thyroid only and may be found 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.)

Treatment

Medical Care

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. 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 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.¹⁴
  • 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.

Surgical Care

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

• Lobectomy with isthmectomy
  • This represents the minimal operation for a potentially malignant thyroid nodule.
  • 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.

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.

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.

Diet

Medication

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.

Thyroid products

These agents treat thyroid hormone deficiency.

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

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.

Dosing

Adult

3-3.5 mcg/kg/d PO for life

Pediatric

Neonate to 6 months: 25-50 mcg/d
6-12 months: 50-75 mcg/d
1-5 years: 75-100 mcg/d
6-12 years: 100-150 mcg/d
>12 years: 150 mcg/d

Interactions

Cholestyramine may decrease absorption; estrogens may decrease response in patients with nonfunctioning thyroid glands; increases effects of anticoagulants; on conversion from hypothyroid to euthyroid may decrease activity of some beta-blockers

Contraindications

Documented hypersensitivity; uncorrected adrenal insufficiency

Precautions

Pregnancy

A - Fetal risk not revealed in controlled studies in humans

Precautions

Maintain TSH between 0.1-0.2 mcIU/mL; menopausal women may develop severe osteoporosis (bone loss); caution in angina pectoris or cardiovascular disease

Antithyroid drug

These agents reduce serum thyroid hormone levels.

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

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.

Dosing

Adult

Nonmetastatic disease: 30-100 mCi IV q3wk
Metastatic disease: 150-200 mCi IV q3wk; treatment ends when scintigraphy is not positive

Pediatric

Not established

Interactions

Uptake is affected by stable iodine, thyroid, antithyroid agents

Contraindications

Documented hypersensitivity; <35 y

Precautions

Pregnancy

X - Contraindicated; benefit does not outweigh risk

Precautions

Pay attention during pregnancy and lactation because drug may pass through placenta and is secreted into milk; may cause bone marrow depression, acute leukemia, anemia, blood dyscrasias, leukopenia, thrombocytopenia, radiation sickness, angina, sinus tachycardia, pruritus, skin rash, hives

Antineoplastic drugs

These agents inhibit cell growth and proliferation.

Cisplatin (Platinol)

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

Dosing

Adult

20-40 mg/m²/d IV for 3-5 d q3wk
Alternatively: 20-120 mg/m² IV once q3wk

Pediatric

Not established

Interactions

Increases toxicity of bleomycin and ethacrynic acid

Contraindications

Documented hypersensitivity; preexisting renal insufficiency; myelosuppression; hearing impairment

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Dosage must be reduced in patients with renal failure; administer adequate hydration before and 24 h after infusion to reduce risk of nephrotoxicity; myelosuppression, ototoxicity, nausea, and vomiting may occur

Doxorubicin (Adriamycin)

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

Dosing

Adult

60-75 mg/m² IV single dose q3-4wk; total dose not to exceed 550 mg/m²

Pediatric

Administer as in adults

Interactions

Verapamil may increase cell toxicity; mercaptopurine worsens toxic effects; streptozocin inhibits metabolism of doxorubicin; cyclophosphamide increases cardiac toxicity; cyclosporine may result in coma and/or seizure; phenobarbital increases elimination; decreases levels of digoxin and phenytoin

Contraindications

Documented hypersensitivity; severe CHF; cardiomyopathy; preexisting myelosuppression; impaired cardiac function; previous treatment with complete cumulative doses of doxorubicin, idarubicin, and/or daunorubicin

Precautions

Pregnancy

D - Fetal risk shown in humans; use only if benefits outweigh risk to fetus

Precautions

Extravasation may result in severe tissue necrosis; caution in patients with impaired hepatic function; at short term, nausea and reddish stain of urine (it is not blood in urine) may occur; may cause toxicity to heart, oral mucosa, hair (alopecia), and hematopoietic system

Follow-up

Further Inpatient Care

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

Further Outpatient Care

• Postoperative therapy and follow-up
  • 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 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.

Deterrence/Prevention

No effective preventive therapy is known.

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. Possible complications include the following:
  • Hypothyroidism¹⁵
  • 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.
• 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.

Patient Education

• Patients who discover a neck deformity or thyroid lumps or have a history of prior exposure to ionizing radiations must consult their physician.
• For excellent patient education resources, visit eMedicine's Endocrine System Center. Also, see eMedicine's patient education article Thyroid Problems.

Miscellaneous

Medicolegal Pitfalls

The main medical and legal problems related to FTC concern vocal cord paralysis due to damage of the recurrent laryngeal nerve, damage of the parathyroid glands that leads to temporary or permanent hypoparathyroidism, and toxic side effects of radioiodine administration. For this reason, always obtain an informed consent to diagnostic procedures and treatment that explains all the procedures and their possible complications.

Special Concerns

Because radioiodine treatment may cause teratogenesis or spontaneous abortions, patients should delay pregnancy for at least one year after radioiodine treatment.

Limited evidence indicates that postsurgical radioiodine administration provides clear benefits in patients who have undergone complete thyroidectomy and adequate lymph node dissection. Strong evidence exists that it is useful in patients younger than 16 years and in those with severe histology.

Although very rare, some cases of malignant transformation of ectopic lingual thyroid tissue have been reported, and only 3 cases of a follicular variant of lingual thyroid tumor have been reported.¹⁶

Multimedia

Media file 1: 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).

Media file 2: This is the same specimen shown in Image 1. 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.

Media file 3: Histologic pattern of a mildly differentiated follicular thyroid carcinoma (250 X). Image courtesy of Professor Pantaleo Bufo at University of Foggia, Italy.

Media file 4: 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.

Media file 5: 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.

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Keywords

follicular thyroid carcinoma, FTC, thyroid cancer, thyroid cancer treatment, thyroid cancer medications, thyroid cancer diagnosis, thyroid cancer symptoms, thyroid cancer pictures, Hürthle cell carcinoma, Hurthle cell carcinoma, papillary carcinoma, tumor

Contributor Information and Disclosures

Author

Luigi Santacroce, MD, Assistant Professor, Medical School, State University at Bari, Italy
Disclosure: Nothing to disclose.

Coauthor(s)

Silvia Gagliardi, MD, Consulting Staff, Department of Surgery, Medical Center Vita, Italy
Disclosure: Nothing to disclose.

Lodovico Balducci, MD, Professor of Oncology and Medicine, University of South Florida College of Medicine; Division Chief, Senior Adult Oncology Program, H Lee Moffitt Cancer Center and Research Institute
Disclosure: Nothing to disclose.

Medical Editor

Philip Schulman, MD, Chief, Medical Oncology, Department of Medicine, Memorial Sloan-Kettering Cancer Center; Clinical Professor, Department of Medicine, New York University School of Medicine
Philip Schulman, MD is a member of the following medical societies: American Association for Cancer Research, American College of Physicians, American Society of Hematology, and Medical Society of the State of New York
Disclosure: celgene Honoraria Speaking and teaching; Amgen Honoraria Speaking and teaching; genetech/idec Honoraria Speaking and teaching

Pharmacy Editor

Francisco Talavera, PharmD, PhD, Senior Pharmacy Editor, eMedicine
Disclosure: eMedicine Salary Employment

Managing Editor

Benjamin Movsas, MD, Vice-Chairman, Department of Radiation Oncology, Fox Chase Cancer Center
Benjamin Movsas, MD is a member of the following medical societies: American College of Radiology, American Radium Society, and American Society for Therapeutic Radiology and Oncology
Disclosure: Nothing to disclose.

CME Editor

Rajalaxmi McKenna, MD, FACP, Southwest Medical Consultants, SC, Department of Medicine, Good Samaritan Hospital, Advocate Health Systems
Rajalaxmi McKenna, MD, FACP is a member of the following medical societies: American Society of Clinical Oncology, American Society of Hematology, and International Society on Thrombosis and Haemostasis
Disclosure: Nothing to disclose.

Chief Editor

Jules E Harris, MD, Clinical Professor of Medicine, Division of Hematology/Medical Oncology, Department of Internal Medicine, University of Arizona College of Medicine at Tucson; Consulting Staff, Arizona Cancer Center
Jules E Harris, MD is a member of the following medical societies: American Association for Cancer Research, American Association for the Advancement of Science, American Association of Immunologists, American Society of Hematology, and Central Society for Clinical Research
Disclosure: GlobeImmune Salary Consulting; Amplimed Consulting fee Consulting; FibroGen Consulting fee Consulting

The progress of the knowledge in molecular bases of thyroid cancers offers new therapeutic targets for FTC treatment and, in the future, prevention. A recent, interesting paper on this subject is Molecular genetics of thyroid cancer: implications for diagnosis, treatment and prognosis from MN Nikiforova and YE Nikiforov (Expert Review of Molecular Diagnostics, January 2008, Vol. 8, No. 1, Pages 83-95).

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