Hurthle Cell Carcinoma

Synonyms and related keywords: Hürthle cell carcinoma; Hurthle cell carcinoma; Ashkenazi cells; oncocytic tumors; oncocytoma; oxyphil tumor; follicular carcinoma, oxyphilic type; differentiated thyroid cancer; Hürthle cell neoplasms; follicular carcinoma of the thyroid; follicular cell neoplasms; oncocytic cells; Hashimoto thyroiditis; Hashimoto's thyroiditis; nodular goiter; toxic goiter; thyroid gland


INTRODUCTION

Background: Hürthle cell carcinoma of the thyroid gland is an unusual and relatively rare type of differentiated thyroid cancer. Hürthle cell cancer accounts for only about 3-10% of all differentiated thyroid cancers; therefore, few institutions have extensive experience with Hürthle cell neoplasms. According to the World Health Organization (WHO), these neoplasms are considered a variant of follicular carcinoma of the thyroid and are referred to as follicular carcinoma, oxyphilic type.

Some investigators believe that this condition is distinct from other follicular cell neoplasms. Hürthle cells are observed in both neoplastic and nonneoplastic conditions of the thyroid gland (eg, Hashimoto thyroiditis, nodular and toxic goiter).

Oncocytic cells in the thyroid are often called Hürthle cells, and oncocytic change is defined as cellular enlargement characterized by an abundant eosinophilic granular cytoplasm as a result of accumulation of altered mitochondria. This is a phenomenon of metaplasia that occurs in inflammatory disorders, such as thyroiditis, or other situations that result in cellular stress. The proliferation of oncocytes gives rise to hyperplastic and neoplastic nodules (Asa, 2004).

The cytological features for Hürthle cell neoplasms are hypercellularity with a predominance of Hürthle cells (usually more than 75%), few or no lymphocytes, and scanty or absent colloid. Hürthle cells are large and polygonal in shape, with indistinct cell borders. They have a large pleomorphic hyperchromatic nucleus, a prominent nucleolus, and intensely pink, fine, granular cytoplasm with hematoxylin-eosin staining. Hürthle cells also are found in other tissues, such as the salivary gland, parathyroid gland, esophagus, pharynx, larynx, trachea, kidney, pituitary, and liver.

Controversy exists about the origin of Hürthle cells, which generally are thought to derive from the follicular epithelium. A Hürthle cell neoplasm is defined generally as an encapsulated thyroid lesion consisting of at least 75% of Hürthle cells. Distinguishing a benign neoplasm from a malignant neoplasm based on cytologic analysis of fine-needle aspiration (FNA) biopsy is not possible. Features such as pleomorphism, anaplasia, hyperchromatism, and atypia also are observed in benign follicular adenomas; therefore, a definitive way to differentiate Hürthle cell carcinoma from Hürthle cell adenoma is based on vascular invasion and/or capsular invasion, as well as on permanent histologic sections or extrathyroidal tumor spread and lymph node and systemic metastases.

Incidence of malignancy in patients with Hürthle cell neoplasms reported in the literature is variable. Reports show that malignancy occurring in these patients is 13-67%. Some lesions considered malignant could be a reflection of permissive histologic interpretation, which may lead to the inclusion of nonneoplastic Hürthle cell lesions with malignant tumors. Obviously, this factor has a major impact in interpreting the natural history of this disease and adds to the controversy about the aggressiveness of Hürthle cell carcinoma. This leads to reported overall mortality rates ranging from 9-28%. Tumor size is an important feature for biological behavior. In a study, a Hürthle tumor that is 4 cm or larger has an 80% chance of histologic evidence of malignancy (Bronner, 1988).

Hürthle cell cancer has the highest incidence of metastasis among the differentiated thyroid cancers. Metastatic disease is reported at the time of initial diagnosis in 10-20% of patients and in 34% of the patients overall. Metastatic disease usually is hematogenous, but lymph node metastasis also is not uncommon and more frequently involves the regional lymph nodes. Some studies arguably show that lymph node metastases at initial diagnosis may not be an unfavorable prognostic factor. The lungs, bones, and central nervous system are the most prevalent sites of metastases.

Pathophysiology: No widely accepted paradigm exists for the pathogenesis of follicular and Hürthle cell cancer of the thyroid. Some evidence suggests that a multistep adenoma-to-carcinoma pathogenesis may be present; however, this concept is not universally accepted. Many of the cells probably develop from preexisting adenomas, but a follicular carcinoma in situ is not recognized pathologically.

Progressive transformation through somatic mutations of genes that are important in growth control are involved in follicular thyroid cancer formation. Low iodide intake is a key environmental factor determining the relative incidence of follicular and papillary cancers. Most follicular adenomas and all follicular carcinomas are thought to have monoclonal origin.

Oncogene activation, particularly by mutation or translocation of the ras oncogene, is common in both follicular adenomas and follicular thyroid carcinomas (around 40%), supporting a role in early tumorigenesis. Such ras oncogene mutations are not specific for follicular tumors and also occur in papillary thyroid cancer (PTC). The ras oncogene frequently is involved in the pathogenesis of Hürthle cell tumors.

An association also was found between overexpression of the p53 gene product and a subset of Hürthle cell carcinomas. Reduced immunoexpression of E-cadherin exists, with a trend to a diffuse cytoplasmic pattern, both in benign and malignant Hürthle cell tumors and in papillary, poorly differentiated, and undifferentiated thyroid carcinomas. Isolated studies indicate overexpression of the N-myc oncogene, tumor growth factor (TGF)-alpha, TGF-beta, insulinlike growth factor (IGF)-1, and somatostatin receptor in Hürthle cell carcinomas.

Cytogenetic abnormalities and evidence of genetic loss are more common in follicular thyroid cancer than in PTC. These abnormalities occur in follicular adenomas, suggesting that cell cycle control, mitotic spindle formation, DNA repair, or more than one of these mechanisms may be impaired in these neoplasms, possibly at an earlier stage.

Activating mutations of genes encoding the thyrotropin receptor and the alpha subunit of the stimulatory G protein also are reported in some follicular carcinomas. These losses are associated particularly with chromosomes 3, 10, 11, and 17. The deletions and/or rearrangements involving the p (short) arm of chromosome 3 are the most common. Loss of a tumor suppressor on chromosome arm 3p has been postulated to be specific for follicular thyroid cancer and may be involved in adenoma-to-carcinoma progression.

Restriction fragment length polymorphism (RFLP) analysis demonstrates that unbalanced losses of genetic material are relatively common in Hürthle cell neoplasms. Loss of heterozygosity from the q (long) arm of chromosome 10 also is detected in oncocytic tumors. Evidence suggests that some Hürthle cell adenomas and carcinomas can express an RET/PTC gene arrangement, which is more unique to papillary thyroid carcinoma. Because of this gene arrangement, Hürthle cell neoplasms supposedly have another subclassification, namely the papillary variant of Hürthle cell cancer (ie, Hürthle cell PTC), in addition to Hürthle cell cancer and adenoma. Clinically, this group of tumors tends to behave like PTC; however, they are more indolent, with a propensity for lymph node metastasis rather than hematogenous spread.

As reported by Asa, many Hürthle cell tumors, whether benign or malignant, show papillary change. This is a pseudopapillary phenomenon, because Hürthle cells tumors have only scant stroma and may fall apart during manipulation, fixation, and processing. True oxyphilic, or Hürthle cell, papillary carcinoma has been reported to comprise from 1-11% of all papillary carcinomas. These tumors have a papillary architecture but are composed predominantly, or entirely, of Hürthle cells (Asa, 2004).

Mitochondrion-related alterations, such as mutations in mitochondrial DNA, also are described in Hürthle cell tumors. Defects of cytochrome c oxidase and the deletion of mitochondrial DNA occur frequently in Hürthle cell tumors and in Hürthle cells of Hashimoto thyroiditis. In one study (Maximo, 2000), almost all Hürthle cells displayed a common deletion and/or somatic mitochondrial point mutations. Activating gene mutations encoding the thyrotropin receptor and the alpha subunit of the stimulatory G protein also are reported in some follicular carcinomas.

DNA content profiles after flow cytometry commonly are abnormal. Hürthle cell neoplasms, including histologically benign tumors, often are aneuploid. This finding parallels with nuclear atypia and anisocytosis. The demonstration of aneuploidy may be a marker for a particularly aggressive clinical behavior compared to euploid tumors.

Frequency:

• In the US: Thyroid cancer is uncommon, and, among all cancers, it accounts for 0.74% in men and 2.3% in women. The average age-adjusted annual incidence for thyroid cancer is less than 40 cases per 1 million people. Among thyroid neoplasms, Hürthle cell carcinomas.

• Internationally: Worldwide frequency likely approximates that of the United States. In general, the annual incidence rate of thyroid cancer in various parts of the world is 0.5-10 cases per 100,000 population. Approximately 3-10% of these cases are Hürthle cell carcinomas.

Mortality/Morbidity: Hürthle cell cancer reportedly behaves in a more aggressive fashion than other well-differentiated thyroid cancers, with a tendency to higher incidence of metastasis and a lower survival rate. This is truer for the lesions that are clearly demonstrated to be malignant and in patients who are considered to be at high risk based on such factors as age, tumor size, invasiveness, and the presence of metastasis. Widely invasive tumors behave more aggressively. Recurrence among patients with Hürthle cell carcinoma is considered to be incurable.

• Mortality rates vary in different series, based on the staging systems used, which consider the patient's age, tumor size, extrathyroidal tumor spread, pathologic classification of the neoplasm (Hürthle cell carcinoma versus adenoma), and the therapeutic approach.

• Overall survival rates reportedly are similar or worse in patients with Hürthle cell carcinoma compared with follicular carcinoma. In a case series of Hürthle cell carcinoma, mortality rates determined at 5, 10, and 20 years were reported at 8%, 18%, and 33%, respectively. Two other case series confirmed a 20-year cause-specific mortality rate of 20-35%. One study showed that when distant metastases were present, the 5-year mortality rate was 65% (Cooper, 1990).

• Morbidity depends on the behavior of the Hürthle cell carcinoma.

Race: Studies usually do not reflect racial differences; however, all races appear to be affected equally.

Sex: Females are affected more commonly than males, with a female-to-male ratio of approximately 2:1.

Age: The age range of patients presenting with this condition is 20-85 years. The mean age usually is 50-60 years, approximately 10 years older than other types of differentiated thyroid cancers.

CLINICAL

History:

• History in patients with a thyroid nodule or a known follicular or Hürthle cell neoplasm is neither sensitive nor specific for a diagnosis of malignancy; however, certain clinical features are more suggestive of malignancy, as follows:

• A palpable mass in the thyroid (most common clinical sign)

• Symptoms of pressure more suggestive of malignancy (eg, dysphagia, dyspnea, coughing, choking spells, hoarseness)

• Rapid growth or significant compressive symptoms

• Pain

• Hürthle cell carcinoma more often is multifocal and bilateral.

• Lymph node metastasis and symptoms confined to metastatic sites can be the first clinical presentation in a subgroup of cases.

• Prior history of head and neck external beam irradiation can be present and should alert the clinician for a possible malignancy. Multifocal and bilateral disease is more common. A family history of thyroid cancer and endocrinopathies also can be present.

• Patients usually are euthyroid; but, in a small percentage of patients, hyperthyroidism or hypothyroidism can be present.

• Other benign thyroid and parathyroid disorders can be observed, as follows:

• Graves disease

• Colloid nodular disease

• Lymphocytic thyroiditis

• Thyroid hyperplasia

• Parathyroid adenoma

• Follicular adenomas

Physical: The most common physical examination finding is a palpable single neck mass. Multiple masses also can be palpated.

• The contralateral lobe also can harbor malignancy given the increased risk of bilateral disease.

• Regional lymph nodes are not as common as papillary carcinoma but can be felt in the neck region and locoregionally.

• The trachea can be compressed and deviated secondary to the mass effect of the tumor. Hoarseness can occur if vocal cord involvement is present.

• Horner syndrome can be present from involvement of the cervical sympathetic ganglia.

• If the tumor extends into the upper mediastinum behind the sternum, the superior mediastinal syndrome may ensue with facial swelling, and dilated veins can be observed.

• A hard fixed thyroid nodule, cervical lymphadenopathy, and vocal cord paralysis are features that may indicate carcinoma.

• Physical findings of metastases and pathologic bone fractures also can be found in long and flat bones.

• Most patients with Hürthle cell cancer and Hürthle cell adenomas are euthyroid. Signs of thyrotoxicosis, although rare, can be present. Either massive tumor burden or functioning metastatic disease causes thyrotoxicosis.

Causes:

• History of radiation to the neck

• Iodide deficiency

• Overexpression of the p53 oncogene

• Activating mutations of genes encoding the thyrotropin receptor and the alpha subunit of the stimulatory of G protein are reported in some follicular carcinomas.

• Somatic mutations of genes important in growth control

• Oncogene activation, particularly by mutation or translocation of the ras oncogene

• Mitochondrion-related alterations (eg, mutations in mitochondrial DNA) also are described.

• In a recent study by Maximo et al, somatic and germline mutation in GRIM-19, a dual function gene involved in mitochondrial metabolism and cell death, is linked to Hürthle cell tumors of the thyroid. This is the first nuclear gene mutation described for a subgroup of Hürthle cell carcinomas (Maximo, 2005).

DIFFERENTIALS

Goiter
Goiter, Diffuse Toxic
Goiter, Nontoxic
Goiter, Toxic Nodular
Graves Disease
Hashimoto Thyroiditis
Thyroid Lymphoma
Thyroid Nodule
Thyroid, Anaplastic Carcinoma
Thyroid, Follicular Carcinoma
Thyroid, Medullary Carcinoma
Thyroid, Papillary Carcinoma
Thyroiditis, Subacute

Other Problems to be Considered:

Hürthle cell adenoma (main differential diagnosis)
Follicular adenoma
Metastatic tumors to the thyroid
Thyroid cysts
Thyrotoxicosis

Metastatic tumors of other Hürthle cell–harboring organs, particularly metastatic renal cell carcinoma and Hürthle cell tumors, originating from the following:

• Salivary glands
  
  
• Pharynx
  
  
• Larynx
  
  
• Trachea
  
  
• Parathyroid gland
  
  
• Esophagus
  
  
• Pituitary
  
  
• Liver

WORKUP

Lab Studies:

• Thyroid function tests

• Thyroid-stimulating hormone (TSH)

• Thyroxine (T4)

• Triiodothyronine (T3)

• Free T4

• Antiperoxidase antibodies

• Antithyroglobulin antibodies

Imaging Studies:

• Thyroid uptake and scan: Typical finding is an area of a cold uptake, which corresponds to the tumor.

• Thyroid ultrasound: Ultrasound usually demonstrates a solid mass, as well as characterizes the solid/cystic nature of the lesion, and it also is helpful to diagnose the enlarged lymph nodes in the neck.

• MRI of the neck: MRI will provide more detailed information about the tumor and its relation to the other neck structures.

• CT scan of the neck: CT scan will provide more detailed information about the tumor and its relation to the other neck structures. CT scan also is helpful for assessment of calcifications.

• Octreotide scintigraphy: This study can be considered for patients with metastatic Hürthle cell carcinoma because evidence suggests that some Hürthle cell neoplasms can express somatostatin receptors.

Procedures:

• Fine-needle aspiration

• FNA can diagnose Hürthle cell neoplasm in most patients; however, the differentiation of Hürthle cell adenoma from Hürthle cell carcinoma cannot be made based on a FNA because vascular and capsular invasion cannot be assessed. Vascular and capsular invasion are the 2 main factors that differentiate carcinoma from adenoma.

• All patients with the cytologic diagnosis of a Hürthle cell tumor should proceed to surgery to ensure that the carcinomas are identified and managed appropriately.

• Frozen section examination

• Frozen section examination of the thyroid gland has variable diagnostic value based on institutional experience.

• This procedure is limited by sampling error, variable thickness, irregularity of the capsule, freezing artifact, difficulty in distinguishing capsular entrapment from invasion, and freezing-induced distortion and collapse of the blood vessels.

• Frozen section has no additional value in most studies; however, in one study, malignant follicular or Hürthle cell carcinoma was established correctly in 78% (Paphavasit, 1997).

• This study requires processing of an average of 6-15 slides per patient, which is impractical in many institutions.

Histologic Findings: Common histological malignancy criteria, such as architectural distortion, cellular atypia, or pleomorphism, are encountered in both benign and malignant follicular adenomas; these histological criteria are not helpful while evaluating a thyroid mass.

The cytologic features for Hürthle cell neoplasms are hypercellularity, with a predominance of Hürthle cells usually above 75%, few or no lymphocytes, and scanty or absent colloid. Hürthle cells are large and polygonal in shape, with indistinct cell borders. They have a large pleomorphic hyperchromatic nucleus, a prominent nucleolus, and intensely pink fine granular cytoplasm with hematoxylin-eosin staining.

Papillary structures and intranuclear inclusions, features that are not ordinarily associated with Hürthle cell lesions, occasionally are noted. The electron microscopic examination of Hürthle cells in tumor formation is unique, revealing a large cytoplasm that is almost completely filled with mitochondria. This examination also reveals large lysosomelike dense bodies and dilated Golgi zones confined to the apical portion of the cytoplasm. Unusual richness of chromatin is clumped against the inner nuclear membrane and nuclei that are observed as round and dense, with separation of fibrillar and granular substances.

Histopathologic differentiation of Hürthle cell carcinoma from Hürthle cell adenoma is based on vascular and capsular invasion. Capsular invasion refers to tumor cell penetration of the capsule of the neoplasm. Vascular invasion is defined by the presence of tumor penetration of blood vessels within or outside of the capsule of the Hürthle cell lesion. Capsular and/or vascular invasion diagnose Hürthle cell carcinoma.

Benign diseases (eg, Hashimoto disease, nodular goiter, toxic goiter) usually have no encapsulation. Hürthle cell changes are part of an inflammatory process.

In a study by Volante et al, the role of galectin-3 and HBME-1 (an antimesothelial monoclonal antibody that recognizes an unknown antigen on microvilli of mesothelial cells) tumor markers, as well as the peroxisome proliferator-activated receptor (PPAR) gamma protein expression, were assessed in oncocytic Hürthle cell tumors, including Hürthle cell adenomas, Hürthle cell carcinomas, and an oncocytic variant of papillary carcinoma. In these 152 Hürthle cell tumors (50 Hürthle cell adenomas, 70 Hürthle cell carcinomas, and 32 oncocytic variant of papillary carcinoma), the sensitivity of galectin-3 was 95.1%, the sensitivity of HBME-1 was 53%, and a combination of galectin-3 and HBME-1 was high at 99%. However, the specificity for both markers was 88%, lower than for non-oncocytic follicular tumors. Interestingly, PPAR gamma protein overexpression was absent in all Hürthle cell adenomas tested and present in only 10% of Hürthle cell carcinomas, similar to other reports that confirm the low prevalence of PAX8-PPAR gamma translocations in Hürthle cell carcinomas.

Staging: Different prognostic criteria and staging systems are used in differentiating thyroid cancer and Hürthle cell cancer. No uniformly accepted staging system and prognostic classification exists for Hürthle cell carcinoma.

The tumor, node, metastases (TNM) system is the most widely used staging system. Such factors as tumor size, patient age, presence of metastases, and major capsular invasion (extensive capsular invasion in multiple sites) are considered in most classification systems during the evaluation of a patient with Hürthle cell carcinoma. The other classification systems used for assessing Hürthle cell carcinoma are conducted with scoring systems, using the generally accepted prognostic factors, such as age, metastasis, extent of disease at operation, and size (AMES) and age, grade, extent, and size (AGES).

TREATMENT

Medical Care: Surgical treatment is the main treatment for patients with Hürthle cell carcinoma. Hürthle cell cancers traditionally are considered radioresistant; however, 10% of metastases take up radioiodine, compared with 75% of metastases from follicular carcinoma. Therefore, radioactive iodide treatment, which is the most useful nonsurgical therapy for patients with recurrent well-differentiated thyroid carcinoma, is not always useful for patients with Hürthle cell carcinoma, causing difficulty in treating recurrence.

• Postoperative iodine-131 scanning

• This scanning usually is performed 4-6 weeks after surgery. No thyroid hormone treatment is administered to the patient in the interim.
• If an uptake exists in the thyroid bed or other sites, a treatment dose of iodine-131 (¹³¹I) is administered, and another total body scan is obtained 4-7 days later.

• Radioactive iodine-131 treatment

• This treatment usually is administered to patients if an uptake occurs in the thyroid bed or elsewhere after postoperative iodine scanning.
• ¹³¹I therapy is administered after surgery for 3 reasons. First, this therapy destroys any remaining normal thyroid tissue, thereby enhancing the sensitivity of subsequent ¹³¹I total-body scanning, and it also increases the specificity of the measurements of serum thyroglobulin for the detection of persistent or recurrent disease. Second, ¹³¹I therapy may destroy occult microscopic carcinoma. Third, the use of a large amount of ¹³¹I therapy allows for total-body scanning, which is a more sensitive test for detecting persistent carcinoma.
• Hürthle cell cancer has a decreased avidity for ¹³¹I; therefore, treatment with radioactive iodide has a limited efficacy.
• Reportedly, approximately 10% of metastases take up radioiodine, compared with 75% of metastases from follicular carcinoma; thus, radioactive iodide treatment, which is the most useful nonsurgical therapy for recurrent well-differentiated thyroid carcinoma, is not always useful in patients with Hürthle cell carcinoma, causing difficulty in treatment for patients who experience recurrences.
• Nevertheless, radioactive iodide treatment is used for patients with most of the Hürthle cell cancers after total and near-total thyroidectomy and in the treatment of patients with recurrent and metastatic Hürthle cell carcinoma.
• Some evidence in the literature suggests using redifferentiation therapy in the form of retinoic acid for some thyroid carcinomas that have lost their capability for radioiodine concentration. This form of therapy also may be considered in patients with Hürthle cell carcinoma that does not take up radioactive iodide, although this is not yet a standard form of therapy.

• Levothyroxine and thyrotropin suppression
  • The growth of thyroid tumor cells is controlled by the TSH, and the inhibition of TSH secretion with T4 improves the recurrence and survival rates of the patient; therefore, T4 should be administered to all patients with thyroid carcinoma, regardless the extent of thyroid surgery and other treatments.
  • Levothyroxine treatment is started after the treatment dose of ¹³¹I is administered.
  • The effective dose in adults is 2.2-2.8 mcg/kg of body weight; children require higher doses.
  • The adequacy of therapy is monitored by measuring serum TSH about 8-12 weeks after the treatment begins; the initial goal being a serum TSH concentration of 0.1 mU/mL or less and a serum triiodothyronine concentration within the reference range.
  • When these guidelines are followed, T4 therapy does not have deleterious effects on the heart or bone.

• External radiotherapy
  • External radiotherapy to the neck and mediastinum is indicated only in patients in whom surgical excision is incomplete or impossible.
  • This therapy also can be considered for tumors that do not take up ¹³¹I.

Surgical Care:

• Surgical treatment is the main treatment for patients with Hürthle cell carcinoma. Surgical treatment is aimed at removal of the entire cancer, thereby minimizing the risk of locally persistent or recurrent disease, providing adequate staging information, minimizing risk without compromise to optimal cancer management, improving efforts for postoperative adjunctive treatment (eg, radioactive iodide), and facilitating follow-up care.

• Generally, extensive surgical treatment is recommended for patients with Hürthle cell carcinomas, usually in the form of a total thyroidectomy, whereas patients with Hürthle cell adenomas generally are treated with a thyroid lobectomy.

• A dilemma exists in standardization of treatment policy for the management of Hürthle cell tumors. Although the majority of series have insufficient patient numbers to allow statistically valid conclusions, a total thyroidectomy generally is considered the treatment of choice for Hürthle cell carcinoma. In general, a lobectomy is performed; however, if Hürthle cell carcinoma is diagnosed on histologic sections, evidenced by vascular and/or capsular invasion, then a complete thyroidectomy is performed in a second surgery. In clinically high-risk cases and in some institutions, a total thyroidectomy is performed as the first surgery based on frozen section results.

• Standard surgical wound care usually is appropriate. Postoperative infection, hematoma, signs of recurrent laryngeal nerve injury (eg, hoarseness), respiratory compromise, and signs of hypoparathyroidism and hypocalcemia should be monitored carefully.

Consultations: Management of thyroid cancer is a team effort, and the following consultations should be obtained:

• Endocrinologist

• Surgeon

• Nuclear medicine specialist

• Pathologist

Diet: No particular diet is recommended, but an iodide-free diet is recommended at least 1 week prior to scanning to minimize the interference.

Activity: Activity may be performed as tolerated.

MEDICATION

The goals or pharmacotherapy are to reduce morbidity, induce remission, and prevent complications.

Drug Category: Thyroid hormones -- Levothyroxine treatment is started after the treatment dose of ¹³¹I is administered.

Drug Name	Levothyroxine (Synthroid, Levoxyl) -- In active form, influences growth and maturation of tissues. Involved in normal growth, metabolism, and development. Children require treatment with higher doses than adults.
Adult Dose	2.2-2.8 mcg/kg/d PO
Pediatric Dose	Suggested dosing: 1-12 months: 7-15 mcg/kg/d PO 1-5 years: 5-7 mcg/kg/d PO 5-10 years: 3-5 mcg/kg/d PO 10-18 years: 2-4 mcg/kg/d PO
Contraindications	Documented hypersensitivity; uncorrected adrenal insufficiency
Interactions	Estrogens may decrease response to thyroid hormone therapy in patients with nonfunctioning thyroid glands; activity of some beta-blockers may decrease when hypothyroid patient is converted to a euthyroid state
Pregnancy	A - Safe in pregnancy
Precautions	Caution in angina pectoris or cardiovascular disease; monitor thyroid status periodically

FOLLOW-UP

Further Inpatient Care:

• Standard postsurgical care usually is adequate. Monitor patients for signs of infection or hematoma formation.

• Clinically monitor patients with hypocalcemic signs, and check calcium levels at least every 12-24 hours. If hypocalcemia is present, immediately treat the patient.

• Monitor patient for signs of laryngeal nerve injury (eg, hoarseness, respiratory compromise).

• If the patient is hospitalized for ¹³¹I treatment, administer antiemetics and adequate hydration.

• Salivary dysfunction secondary to uptake in salivary glands can be prevented by adequate hydration and sucking on candies.

• Follow effective radiation precautions.

Further Outpatient Care:

• Signs of hypothyroidism should be monitored after surgical treatment.
• Levothyroxine therapy usually should be started after the treatment dose of ¹³¹I is administered.
• Monitor patient for signs of hypocalcemia.
• Monitor patient's calcium levels.
• Before scanning, instruct the patient to avoid iodine-containing medications and iodine-rich foods. Measure urinary iodine in doubtful cases.
• In women of childbearing age, pregnancy must be ruled out.
• Patients should be instructed carefully about radiation precautions prior to ¹³¹I treatment; patients should follow the instructions meticulously when sent home.
• Thyroxine treatment

• The adequacy of therapy is monitored by measuring serum TSH approximately 8-12 weeks after treatment begins, with the initial goal being a serum TSH concentration of 0.1 mU/mL or less and a serum T3 concentration within the reference range.
• In patients who are at low risk and considered cured, the dose of T4 is decreased to maintain a low, but detectable, serum TSH concentration (0.1-0.5 mU/mL). In higher-risk patients, higher doses are continued, targeting a serum TSH concentration of 0.1 mU/mL or less.

• Clinical and ultrasonographic examinations

• Thyroid bed and lymph node areas should be examined routinely. Ultrasonography is recommended in patients at high risk for recurrent disease and in any patient with suspicious clinical findings. Palpable lymph nodes that are small, thin, or reduced in size after an interval of 3 months can be considered benign.
• Serum thyroglobulin concentrations were undetectable in a group of patients receiving T4 treatment who have isolated lymph node metastases; therefore, undetectable values do not rule out metastatic lymph node disease. If the patient is thought to have metastases, a lymph node biopsy may be performed.

• Thyroglobulin measurement

• Thyroglobulin is produced only by normal or neoplastic thyroid follicular cells and should be undetectable in patients who have been treated with surgery and radioablation.
• In the follow-up care of patients, thyroglobulin is used as a marker of residual disease, of disease recurrence, and as a prognostic factor.
• Thyroglobulin concentrations as low as 1 ng/mL or even lower can be detected with current assays.
• Antithyroglobulin antibodies, which are found in approximately 15% of patients with thyroid carcinoma, can alter tests for thyroglobulin artifactually. These antibodies always should be checked when serum thyroglobulin is measured.

• Chest x-ray films: Most patients with abnormal x-ray findings have detectable serum thyroglobulin concentrations; therefore, this study might not have an additional value in diagnosing metastatic disease, but it still can have a limited diagnostic value in a subgroup of patients.
• Iodine-131 total body scanning

• The uptake of ¹³¹I and the level of TSH concentration determine the accuracy of total body scanning. In patients whose levothyroxine is held, the serum TSH concentration usually should be higher than 30 mU/mL when the total-body scan is performed. Intramuscular injection of recombinant human thyrotropin is a promising new alternative because T4 treatment does not need to be discontinued and the adverse effects are minimal. For routine diagnostic scans, 2-5 mCi (74-185 mBq [millibecquerel]) of ¹³¹I is administered; higher doses may reduce the uptake of a subsequent therapeutic dose of ¹³¹I.
• Scanning is performed, and uptake, if any, is measured 3 days after the dose has been administered. In certain situations, an uptake cannot be detected with diagnostic scans when 2-5 mCi of ¹³¹I is administered, and it may be detectable after the administration of 100 mCi. This is the rationale for administering 100 mCi (or more) of ¹³¹I in patients with elevated serum thyroglobulin concentrations (usually levels >10 ng/mL after T4 has been withdrawn). If this approach is taken, total-body scanning should be performed 4-7 days later.

• If the serum thyroglobulin concentration becomes detectable in patients receiving T4, the T4 should be withdrawn, an ¹³¹I total-body scan should be obtained, and serum thyroglobulin should be measured. If any uptake is detected or the serum thyroglobulin concentration rises above the previous level, ¹³¹I therapy should be administered.

• In the absence of ¹³¹I uptake, a CT scan of the neck and lungs, bone scintigraphy, and scintigraphy using a less-specific tracer (eg, thallium, tetrofosmin, fluorodeoxyglucose) should be considered strongly in patients with Hürthle cell carcinoma who are known to have no or low uptake.

In/Out Patient Meds:

• Levothyroxine: The dose should be titrated to a subnormal TSH concentration.

Deterrence/Prevention:

• No specific prevention is available, although avoidance of radioactive exposure and adequate iodide intake can be considered preventive measures.

Complications:

• Surgical complications include laryngeal nerve injury and transient or permanent hypoparathyroidism manifested as hypocalcemia. Hypothyroidism can occur if replacement therapy is inadequate. Hyperthyroidism can occur if the patient is overtreated with levothyroxine. Surgical scars in the neck also can be cosmetically disturbing in certain individuals.

• Surgical complications

• Recurrent laryngeal nerve injury
• Hypoparathyroidism (transient, permanent)

• Infection

• Hematoma

• Nonsurgical complications

• Acute adverse effects
  • Nausea or vomiting sialadenitis
  • Radiation-induced
  • Thyroiditis
  • In metastatic cases, radiation-induced fibrosis of the lung when using large doses of ¹³¹I (>150 mCi) administered at short intervals
  • Mild pancytopenia observed after repeated ¹³¹I therapy, particularly in patients with bone metastases who also have received external radiotherapy

• Genetic defects and infertility
  • Transient reduction in spermatogenesis
  • Transient ovarian failure
  • Increased frequency of miscarriages

• Carcinogenesis and leukemogenesis - Risk of secondary carcinoma or leukemia increased only in patients who have received a high cumulative dose of ¹³¹I (>500 mCi) and those who also receive external radiation therapy

Prognosis:

• Hürthle cell carcinomas behave in a more aggressive fashion than other well-differentiated thyroid cancers, as evidenced by a higher incidence of metastasis and a lower survival rate. Hürthle cell carcinomas produce thyroglobulin. In addition, most Hürthle cell carcinomas have decreased avidity for ¹³¹I; therefore, treatment with radioactive iodide has limited efficacy.

• In some series, nuclear aneuploidy is present in as many as 90% of patients with Hürthle cell carcinoma; in some studies, this condition is shown to be associated with an adverse prognosis.

Patient Education:

• Patients should be advised not to get pregnant for at least 1 year after treatment.

• Radiation precautions should be explained in length and clearly to a patient who will be receiving radioactive iodine treatment.

• The need for life-long levothyroxine treatment should be explained to the patients.

• For excellent patient education resources, visit eMedicine's Endocrine System Center. Also, see eMedicine's patient education article Thyroid Problems.

MISCELLANEOUS

Medical/Legal Pitfalls:

• Failure to explain potential surgical complications

• Failure to explain the need for levothyroxine treatment

• Pregnancy

• ¹³¹I should not be administered to pregnant women.

• Pregnancy should be ruled out prior to treatment.

• Postponement of pregnancy for 1 year after treatment with ¹³¹I is recommended.