Note: Large images and tables on this page may necessitate printing in landscape mode.
Copyright 2007 The McGraw-Hill Companies. All rights reserved.
Current Otolaryngology > X. Thyroid & Parathyroid > Chapter 41. Disorders of the Thyroid Gland >
Anatomy & Histology
The normal thyroid gland is located anterior to the trachea and midway between the apex of the thyroid cartilage and the suprasternal notch (Figure 411). Important neighboring posterior structures include the four parathyroid glands situated behind the upper and middle thyroid lobes, and the recurrent laryngeal nerves coursing along the trachea. The thyroid consists of two pear-shaped lobes connected by an isthmus. The typical dimensions of the lobes are 2.54.0 cm in length, 1.52.0 cm in width, and 1.01.5 cm in thickness . Also, in about 50% of patients , a small pyramidal lobe is present at the isthmus or adjacent part of the lobes . Microscopically, the thyroid consists of varying- sized follicles consisting of a central collection of colloidal material surrounded by a single layer of epithelial cells .
Figure 411.
Gross anatomy of the thyroid gland.
(Reproduced, with permission, from Greenspan FS: Basic and Clinical Endocrinology. Originally published by Appleton & Lange. New York: The McGraw-Hill Companies, 1983.)
A normal thyroid gland weighs approximately 1020 g, depending on dietary iodine intake, age, and weight. The thyroid gland usually grows posteriorly and inferiorly, since it is limited from upward extension by the sternothyroid muscle. In large multinodular goiters, substernal extension is not uncommon.
The thyroid gland has a rich blood supply, derived from the superior , inferior, and the small inferior ima artery (Figure 412). Venous flow returns via multiple surface veins draining into the superior, lateral, and inferior thyroid veins.
Figure 412.
Arterial and venous blood supply of the thyroid gland.
(Reproduced, with permission, from Lindner HH: Clinical Anatomy. Originally published by Appleton & Lange. New York: The McGraw-Hill Companies, 1989.)
Thyroid Hormones
Thyroid Hormone Synthesis
The synthesis of T 4 (thyroxine) and T 3 (triiodothyronine) occurs both within the cell and at the cell -colloid junction. The key components of thyroid hormone synthesis include thyroglobulin, a large thyroid hormone precursor sequestered in the colloid and thyroid peroxidase that catalyzes the iodination of thyroglobulin and the coupling of thyroglobulin residues to form T 4 and T 3 . The six essential steps to thyroid hormone synthesis are (1) active uptake of iodide, (2) oxidation of iodide and iodination of thyroglobulin, (3) coupling of iodotyrosine molecules within thyroglobulin to form T 3 and T 4 , (4) proteolysis of thyroglobulin and the release of free iodothyronines and iodotyrosines, (5) deiodination of iodotyrosines within the thyroid and recycling of the liberated iodide, and (6) in certain situations, deiodination of T 4 to T 3 (Figure 413). Thyroid hormone synthesis is mostly controlled by the hypothalamic- pituitary -thyroid axis, as illustrated in Figure 414.
Figure 413.
Thyroid hormone synthesis.
Figure 414.
The hypothalamic-pituitary thyroid axis. The hypothalamus secretes thyroid-releasing hormone (TRH), which causes the pituitary to release thyroid stimulating hormone (TSH). In turn , TSH stimulates most of the thyroid hormone formation of T 4 and some of the formation of T 3 . T 4 and T 3 negatively feed back on the hypothalamus and pituitary, completing the regulatory cycle.
Thyroid Hormone Transport
Thyroid hormones are mostly bound to carrier proteins ; 99.96% of T 4 and 99.60% of T 3 are bound in the serum (Figure 415). The small fraction of unbound T 4 and T 3 hormones are responsible for biologic activity. Thyroid hormones are transported throughout the body bound to three carrier proteins in the serum: (1) thyroxine-binding globulin (TBG); (2) thyroxine-binding prealbumin (TBPA), also known as transthyretin; and (3) albumin.
Figure 415.
Thyroid hormone structure and biologic activity.
Metabolism of Thyroid Hormones
Biologic activity is dependent on the degree and location of iodination (see Figure 415). T 3 is 38 times more potent than T 4 . T 4 is the predominant circulating thyroid hormone, whereas T 3 is the main peripherally active hormone. 5'-deiodinase converts T 4 into the active form T 3 in the peripheral tissues. Certain drugs can inhibit the conversion of T 4 to T 3 : propylthiouracil, amiodarone, ipodate, glucocorticoids, and propranolol. T 4 has a half-life of approximately 7 days, whereas T 3 has a half-life of 1 day.
Assessment of Thyroid Function
Thyroid Function Tests
The most commonly used thyroid function tests in clinical practice are serum immunoassays for thyroid-stimulating hormone (TSH, or thyrotropin) and free thyroxine (or free T 4 , also known as FT 4 ). TSH can be used alone in screening for overt thyroid disease, but both TSH and FT 4 are needed for the diagnosis, especially if pituitary or hypothalamic disease is suspected. With a normal hypothalamus and pituitary, TSH maintains an inverse relationship with FT 4 . Figure 416 provides an algorithm for the evaluation of thyroid function tests. The common profiles of thyroid function tests in different disease states are outlined in Table 411. TSH is an extremely sensitive pituitary indicator of thyroid disease, but it requires 46 weeks to reflect changes in thyroid hormone levels. FT 4 is a less sensitive indicator of thyroid hormone production, but it may be helpful in monitoring more acute changes in thyroid activity. In evaluating hyperthyroidism, it may also be helpful to obtain a total T 3 or FT 3 to rule out T 3 thyrotoxicosis .
Figure 416.
Diagnostic approach to thyroid function tests. TSH, thyroid-stimulating hormone.
Table 411. Patterns of Thyroid Function Tests.
TSH
Free T 4
T 3
Diagnosis
Normal
Normal
Normal
Euthyroid
Normal
Low normal or low
Low or normal
Central hypothyroidism or sick euthyroid or drugs
High
Low
Normal or low
Primary hypothyroidism
High
Normal
Normal
Subclinical hypothyroidism
High
High
High
TSH resistance syndrome*
Low
High or normal
High
Hyperthyroidism
Low
Normal
Normal
Subclinical hyperthyroidism or drugs
Low
Normal
High
T 3 toxicosis*
Low
Low
Low
Central hypothyroidism or sick euthyroid or drugs
*Denotes rare conditions
Thyroid-Stimulating Hormone Immunoassay
The TSH assays currently used are immunoassays based on two monoclonal antibodies detecting different epitopes of the TSH. Most laboratories use either a second- or third-generation TSH assay, which detects levels as low as 0.10 and 0.01 mU/L respectively. TSH is a sensitive measure of the response of the pituitary gland to circulating FT 4 levels.
TSH levels are elevated mostly in primary hypothyroidism and are accompanied by a low level of FT 4 . Table 412 lists situations in which the TSH is elevated (other than in hypothyroidism), including drugs, recovery from an acutely ill state, acute psychiatric admission, and the very rare TSH-secreting pituitary tumor.
Table 412. Drugs and Their Effects on Thyroid Function Tests.
True hyperthyroidism
Iodine and iodine-containing drugs (amiodarone, IV contrast), lithium, interferon alfa, interleukin 2
True hypothyroidism
Iodine and iodine-containing drugs (amiodarone, IV contrast), lithium, interferon alfa, interleukin 2
Amiodarone, iodine and iodine-containing substances, glucocorticoids, propylthiouracil, propranolol
A decreased TSH level should be interpreted in conjunction with the FT 4 level. A decreased TSH level with an elevated FT 4 level suggests primary hyperthyroidism. A low FT 4 level with a normal to decreased TSH level may indicate secondary or central hypothyroidism (< 5% of all cases of hypothyroidism), which are due to a pituitary or hypothalamic tumor. The diagnosis can be confirmed by performing a thyrotropin-releasing hormone (TRH) stimulation test, with elevation of the TSH 30 and 60 minutes postinjection, but this test is rarely necessary. A number of situations, including drugs and nonthyroidal illness , can also cause both low TSH and FT 4 levels (see Table 411).
Free Thyroxine Immunoassay (FT 4 )
FT 4 is an assay measuring the serum concentration of T 4 . It has largely replaced indirect measurements of FT 4 concentrations, such as the free T 4 index (FT 4 I), which is the product of resin T 3 (or T 4 ) uptake and total T 4 . Most laboratories use a chemiluminescent immunoassay to measure FT 4 levels. It is valid in most cases, except in patients with very high or low thyroid-binding proteins or severe illness. Under these circumstances, the measurement of FT 4 levels by equilibrium dialysis is more reliable. FT 4 is elevated in hyperthyroidism and decreased in hypothyroidism. Table 412 lists the conditions that affect FT 4 levels. Of note, the antiepileptic drugs phenytoin, carbamazepine, and rifampin can cause a significantly increased hepatic metabolism of T 4 . Also, drugs and illness rarely suppress the TSH to undetectable levels. The measurement of FT 4 levels by dialysis is spuriously elevated by heparin, which activates lipoprotein lipase, which in turn generates fatty acids that displace T 4 from TBG.
Total Triiodothyronine (T 3 )
Total T 3 measures both the free and bound T 3 in circulation. Total T 3 is helpful in diagnosing hyperthyroidism with elevated T 3 levels but normal T 4 levels (ie, T 3 toxicosis). The preferential secretion of T 3 can be seen in early Graves' disease or toxic multinodular goiter.
Free T 3
Free T 3 (FT 3 ) is a newer test that allows for the direct measurement of FT 3 levels via chemiluminescent assay or radioassay.
Antithyroid Peroxidase Antibody
Thyroid peroxidase (TPO) is the key enzyme that catalyzes the iodination of thyroglobulin and the coupling of iodinated tyrosyl residues to form T 3 and T 4 . TPO is located on the microvilli at the thyroid-colloid interface. Almost all patients with Hashimoto's thyroiditis have antithyroid peroxidase (anti-TPO) antibodies presentthese antibodies are usually measured to diagnose Hashimoto's thyroiditis. A large number of patients with Graves' disease also have anti-TPO antibodies. Both anti-TPO and thyroglobulin antibodies are positive in about 510% of normal subjects.
Thyroid Stimulating Immunoglobulin
Thyroid stimulating immunoglobulin (TSI) of the TSH receptor antibody is an indirect test that confirms the diagnosis of Graves' disease. TSI is positive in approximately 90% of patients with Graves' disease, and negative both in normal patients and patients with Hashimoto's thyroiditis. Patient serum is incubated with either human thyroid cell culture or hamster ovary cells that express recombinant human TSH receptor; cyclic adenosine monophosphate (AMP) activity is measured. TSI is also of diagnostic value in patients with normal thyroid function who have exophthalmos. The measurement of TSI is helpful during pregnancy high titers increase the risk of neonatal thyrotoxicosis.
Serum Thyroglobulin
Serum thyroglobulin is the precursor protein required for the synthesis of T 4 and T 3 . The normal measure is < 40 ng/mL in individuals with normal thyroid function, and < 5 ng/mL in patients after a thyroidectomy. Thyroglobulin is raised when the thyroid is overactive, such as with Graves' disease or multinodular goiter. In very large goiters, the elevated levels of thyroglobulin reflect the gland size . In subacute or chronic thyroiditis, thyroglobulin is released as a consequence of tissue damage.
Thyroglobulin is a very useful marker for thyroid cancer, both to assess treatment efficacy and to monitor for recurrence after total thyroidectomy and radioiodine 131 I therapy . Because thyroglobulin is made only by the thyroid gland, its level serves as an indicator of the presence of thyroid tissue, as in well-differentiated thyroid cancer. Under these circumstances, a thyroglobulin level of > 10 mg/dL indicates the presence of metastatic disease. It is necessary to measure for endogenous thyroglobulin antibodies as part of interpreting the measurement of the thyroglobulin level. These antibodies can interfere with the assay and give spuriously high or low levels, depending on the measurement method used.
Radioactive Iodine Uptake & Scan
Radionuclide imaging of the thyroid with 123 I or 99m Tc is useful in evaluating the functional activity of the thyroid. The two tests that use radioactivity to assess the thyroid are the radioactive uptake and scan. Radioactive uptake evaluates thyroid function by reporting the percentage uptake of iodine, whereas the scan produces an image of the distribution of iodine in the thyroid. The radioactive scan gives information regarding the size and shape of the thyroid, as well as information about nodules that are either functioning ("hot" nodules) or nonfunctioning ("cold" nodules). 123 I can be used to assess both radioactive uptake and scan, but 99m Tc can only be used for scanning. A 99m Tc study gives results within 30 minutes, whereas 123 I images are obtained at 46 hours and at 24 hours. 123 I delivers less radiation than 131 I because of its short half-life of 13 hours and the absence of beta radiation. Its gamma photo energy of 159 keV is ideally suited for thyroid scanning. Both 123 I and 99m Tc are contraindicated in pregnancy.
123 I allows assessment of the turnover of iodine by the thyroid gland. After 100200 Ci of 123 I, radioactivity over the thyroid area is measured by scintigraphy at 4 or 6 hours and at 24 hours. The normal ranges of uptake vary with iodine intake. In areas of low iodine intake and endemic goiter, uptake may be as high as 6090%. In the United States, with a relatively high intake, the normal uptake is 515% at 6 hours, and 830% at 24 hours.
Both 123 I uptake and scan are useful in delineating the cause of hyperthyroidism. Uptake is elevated in thyrotoxicosis due to Graves' disease and toxic multinodular goiter. Uptake is low in subacute thyroiditis, the active phase of Hashimoto's thyroiditis with the release of preformed hormone, exogenous thyroid hormone ingestion , excess iodine intake (from amiodarone, iodinate contrast dyes, or kelp pills), and hypopituitarism. More rare causes include ectopic thyroid hormone production from HCG (human chorionic gonadotropin), struma ovarii, and metastatic follicular thyroid carcinoma . 131 I uptake and scans are very useful in monitoring the recurrence of well-differentiated thyroid cancer. Typically, 23 mCi of 131 I is given to the patient, and images of the thyroid and the whole body are taken to look for recurrence or metastases. If the patient is treated with high-dose 131 I to ablate remnant thyroid cancer, a post-treatment thyroid and whole-body scan is often helpful to look for tumor tissue that weakly uptakes iodine.
Nonthyroidal Illness & Thyroid Function Tests
Severely ill patients exhibit altered thyroid function tests. Most hospitalized patients have lower serum T 3 concentrations due to inhibition of the peripheral conversion of T 4 to T 3 by 5' deiodinase. Severely ill patients (50% of patients in the ICU and 1520% of hospitalized patients) can have a low serum T 4 level. This low level is mostly due to very low levels of thyroid-binding proteins, but the exact mechanism remains to be elucidated. The degree of T 4 depression has been directly correlated with overall patient outcome. Most hospitalized patients also have slightly depressed but detectable levels of TSH. It has been suggested that hospitalized patients may have a subtle form of central hypothyroidism as a protective mechanism against their ill health and an increased catabolism. Studies have shown that administering thyroxine to patients who are ill has no benefit and may, in fact, be harmful . In the recovery phase of nonthyroidal illness, the TSH level tends to transiently rise before it returns to normal levels.
The assessment of thyroid function in the setting of nonthyroidal illness is difficult and should be undertaken only when there is a strong suspicion of thyroid disease. A straightforward approach to thyroid function tests in a patient who is hospitalized is to measure both TSH and FT 4 . An elevated TSH, especially > 20 U/mL, is suggestive of primary hypothyroidism. In 75% of cases, patients with an undetectable TSH using a third-generation TSH assay are likely to have primary hyperthyroidism. A depressed but detectable TSH usually accompanied by a low T 4 level could indicate nonthyroidal illness, drug effect, subclinical hyperthyroidism, or central hypothyroidism. In these situations, other aspects of the patient history and examination may be helpful in making the diagnosis. The presence of a goiter, known pituitary disease, and thyroid test results obtained before the illness can direct the diagnosis and treatment. If nonthyroidal illness or a drug effect is highly suspected, the intermittent monitoring of thyroid function tests may be warranted.
Dayan CM. Interpretation of thyroid function tests. Lancet. 2001;357(9256):619. (A practical approach to thyroid function tests with a focus on common test pattern interpretation and the avoidance of pitfalls.) [PMID: 11558500]
Klee GG, Hay ID. Biochemical testing of thyroid function. Endocrinol Metab Clin North Am. 1997;26(4):763. (A more comprehensive analysis of thyroid function tests.) [PMID: 9429859]
Physical Examination
There are three basic maneuvers in examining the thyroid. The patient should be seated with only a slightly flexed neck to relax the sternocleidomastoid muscles . The thyroid should first be observed while the patient swallows a sip of water. An enlarged gland or nodules can be observed as the gland moves up and down. The thyroid gland should then be palpated from behind the patient, with the middle three fingers on each lobe of the gland. While the patient swallows, thyroid nodules or an enlargement can be noted as the gland passes beneath the examiner 's fingers. A normal thyroid is usually found to be 2 cm in length and 1 cm in width. A generalized enlargement of the thyroid is called a diffuse goiter (from gutta , Latin for "throat"), whereas an irregular enlargement is termed a nodular goiter.
Thyroid Masses
Thyroid Nodules
General Considerations
Thyroid nodules are common, with a 4% prevalence in the United States and a male-to- female ratio of 4:1. Although the incidence of thyroid cancer is only 0.004% per year, each nodule should be assessed to rule out the possibility of thyroid cancer.
Clinical Findings
The initial evaluation of a thyroid nodule involves a careful history taking and physical examination (Table 413). Age is an important risk factor, with adults younger than 30 or older than 60 years of age carrying a high risk for thyroid cancer. A patient family history of medullary thyroid carcinoma or personal radiation exposure, especially when young, should alert the physician to the possibility of thyroid cancer. Recent growth, or evidence of hoarseness, dysphagia, or obstruction, should also raise suspicion. An ultrasound study is particularly helpful in distinguishing a cyst from a solid nodule and also in identifying other nonpalpable nodules. Ultrasound can also identify nodules that are more concerning for malignancy, that is, those that have microcalcifications, irregular borders, and increased blood flow.
Table 413. Clinical Evaluation of Thyroid Nodules.
Low Risk
High Risk
History
Family history of goiter
Family history of medullary cancer
History of head and neck radiation
Recent growth of nodule
Hoarseness, dysphagia
Epidemiology
Older woman
Young adult, male, or child
Physical exam
Soft nodule
Multinodular goiter
Solitary, firm nodule
Vocal cord paralysis
Firm lymph nodes
Serum factors
High titer of thyroid antibodies, hyper- or hypothyroidism
123 I Thyroid scan
"Hot nodule"
"Cold nodule"
Ultrasound of thyroid
Pure cystic lesion
Solid or semicystic lesion
Thyroxine therapy
Regression
Increase in size of mass
After primary thyroid disease is ruled out with normal thyroid function tests, the diagnostic procedure of choice is a fine-needle aspiration (FNA) biopsy of the thyroid nodule. Indications for biopsy include solitary thyroid nodules, multiple nodules, or dominant or growing nodules that exist within a multinodular goiter. Although in the past, multinodular goiters and multiple nodules were thought to have a decreased incidence of thyroid cancer, recent data have suggested that the incidence of thyroid cancer may be higher. FNA biopsy is performed using a 23- to 25-gauge needle with or without local anesthesia, and usually with ultrasound guidance. Several passes are made into the thyroid nodule, and the aspirated material is used in thin smear slides that are both air dried and alcohol preserved.
Cytopathologic examinations are typically reported as benign; suspicious or indeterminate (eg, follicular neoplasms); malignant; or nondiagnostic. One review of thyroid biopsy reported that 70% of FNAs were benign , 10% were suspicious or were follicular neoplasms, 5% were malignant, and 15% were nondiagnostic. Cystic lesions yield serous fluid with immediate involution of the nodule. Although a malignant growth is less likely to occur in a purely cystic lesion, the fluid should still be sent for cytologic examination. If the cyst has tissue in the wall, then FNA of this region should be performed under ultrasound guidance. FNA is considered nondiagnostic if the specimens show a lack of follicular epithelium or the presence of excessive bloody dilution. A recent review of more than 5000 FNA procedures revealed an accuracy of over 95%, with a false-negative rate of 2.3% and a false-positive rate of 1.1%.
Treatment
An algorithm of thyroid nodule management can be found in Figure 417. The management of a malignant growth, as indicated by FNA, requires total thyroidectomy, with careful attention paid to local, palpable lymph nodes that may require neck dissection at the time of surgery. Follicular adenomas are often deemed "indeterminate" because they are difficult to distinguish from follicular carcinomas on FNA. Evidence of vascular or capsular invasion is required for the diagnosis of follicular carcinoma. Roughly 1020% of all suspicious lesions actually prove to be follicular carcinoma on excision . A 123 I scan can be helpful in distinguishing between an adenoma or carcinomaif the lesion is hyperfunctioning or "hot," then it is unlikely to be malignant and can be observed or radioablated if the patient is hyperthyroid. In contrast, if the lesion is hypofunctioning or "cold," then the patient is referred for partial thyroidectomy to rule out follicular carcinoma.
Figure 417.
Algorithm for the management of thyroid nodules.
Benign thyroid nodules are usually followed up clinically; these growths may enlarge, stay the same size, or involute. Ultrasound is particularly helpful in follow-up measurements. Suppressive therapy of benign thyroid nodules is controversial . Most studies have not shown regression of solitary nodules with exogenous thyroxine, whereas some studies have shown a 2030% reduction. Currently, most authorities do not recommend L -thyroxine therapy in the treatment of solitary nodules. Nodules that increase in size raise concern for a malignant growth and require reexamination with repeat FNA or surgical removal. Cystic lesions quickly involute on aspiration but are more prone to recur. In addition, FNA of cystic lesions can yield nondiagnostic cytology because of the difficulty of performing a biopsy of the thin cystic wall. Repeat FNAs are often required, and ultimately surgical removal may be needed. One small randomized trial showed that suppressive therapy for cystic nodules was not helpful.
An increasing number of incidental thyroid nodules are being identified as a result of the frequent use of ultrasonography by the primary care physicians in the evaluation of the thyroid gland. It is recommended that patients with nodules that are 1.0 cm or that have suspicious sonographic appearance proceed with FNA-guided ultrasound. Incidental thyroid nodules identified on positron emission tomography (PET) scans should undergo particularly careful evaluation because up to two thirds of these hypermetabolic lesions have been found to be cancers.
Multinodular Goiter
General Considerations
With multinodular goiter, the thyroid gland is usually large, weighing from 60 to 1000 g. On pathologic examination, it contains nodules that vary in size, number, and appearance. Some nodules contain colloid and others are cystic, containing brown fluid that indicates previous hemorrhage. Some of the nodules have autonomous function. The spectrum of function of these goiters ranges from the euthyroid state, with some degree of autonomous function, to thyrotoxicosis (eg, toxic multinodular goiter).
Clinical Findings
The principal clinical features of a nontoxic goiter are the same as those of a thyroid enlargement. Large goiters can cause dysphagia, a choking sensation , and inspiratory stridor. Hemorrhage into a nodule can present with acute painful enlargement and may induce or enhance obstructive symptoms.
Treatment
The treatment for an enlarged asymptomatic multinodular goiter is suppressive therapy. Up to 60% of these goiters respond to such treatment. Long- term treatment is required because stopping the suppression results in regrowth of the gland. It is important to start with a low dose of L -thyroxine and carefully monitor the FT 4 and TSH levels, aiming for a level of FT 4 in the normal range and a level of TSH in the lownormal range. Careful follow-up is necessary to monitor both for the development of autonomous function within the gland and for thyrotoxicosis. Surgery should be considered in patients when either the gland grows on suppressive treatment or there are obstructive symptoms. Surgical complications, such as recurrent laryngeal nerve damage and hypoparathyroidism, can be as high as 710%. Radioactive iodine treatment can result in a reduction of the thyroid volume and is safe in the treatment of a nontoxic multinodular goiter. Hypothyroidism can occur in 2240% of subjects within 5 years after 131 I treatment.
For a toxic multinodular goiter, control of the hyperthyroid state with antithyroid drugs followed by subtotal thyroidectomy is the treatment of choice. If the patient is a poor surgical candidate, then a 131 I treatment dose is a reasonable option. Patients who have some degree of autonomous function in their multinodular goiter can develop overt thyrotoxicosis when exposed to an iodine load (eg, amiodarone treatment or IV contrast). This iodide-induced thyrotoxicosis can be treated with methimazole and beta-adrenergic blockade. 131 I treatment may not be possible because of the large iodine pool. Total thyroidectomy is curative but is feasible only if the patient can withstand the stress of surgery.
Hermus AR, Huysmans DA. Treatment of benign nodular thyroid disease. N Engl J Med. 1998;338(20):1438. (Practical review of the management and treatment of nontoxic and toxic multinodular goiter.) [PMID: 9580652]
Meier CA. Thyroid nodules: pathogenesis, diagnosis and treatment. Baillieres Best Pract Res Clin Endocrinol Metab. 2000;14:559. (Review of currently recommended approach to thyroid nodules.) [PMID: 11289735]
Siegel RD, Lee SL. Toxic nodular goiter. Toxic adenoma and toxic multinodular goiter. Endocrinol Metab Clin North Am. 1998;27(1):151. (Practical review of current theories of the pathogenesis and treatment of solitary toxic adenoma and toxic multinodular goiter.) [PMID: 9534034]
Thyroid Cancer
Thyroid cancer represents only 1% of all cancers, with an estimated incidence of 19,500 new cases in 2001. In the past three decades, the incidence of thyroid cancer has increased by almost 50%; however, mortality rates have declined by 20%. This may be due to earlier detection by FNA and subsequent treatment. There are four main pathologies encountered in thyroid cancer: papillary, follicular, medullary, and anaplastic carcinomas (Table 414).
Table 414. Frequency of Thyroid Cancer.
Cancer
Percentage
Papillary carcinoma
75%
Follicular carcinoma
16%
Medullary carcinoma
5%
Undifferentiated
3%
Other
(Lymphoma, fibrosarcoma, squamous cell carcinoma, teratomas, hemangioendothelioma, and metastatic carcinomas)
1%
Papillary Carcinoma
General Considerations
Papillary carcinoma is the most common thyroid cancer, representing 75% of all thyroid cancers. It has the best prognosis , with a 5% mortality rate at 20 years for patients with no evidence of local invasion at diagnosis. In addition to a history of childhood exposure to radiation, risk factors for papillary carcinoma include familial papillary carcinoma, Cowden syndrome (eg, multiple hamartomas of the skin and mucous membranes), and familial adenomatous polyposis coli.
Clinical Findings
Microscopically, papillary carcinoma consists of single layers of thyroid cells arranged in avascular projections or papillae, which manifest as large pale nuclei, intranuclear inclusion bodies, and anaplastic features. "Psammoma bodies" are laminated calcified spheres and are usually diagnostic of papillary carcinoma. Papillary carcinoma can be either purely papillary or mixed with follicular carcinoma; both are treated with similar therapies. Certain histopathologic variants, such as tall cell, columnar cell, and diffuse sclerosing types, are associated with a higher risk of recurrence.
Papillary carcinoma typically has an indolent natural history. Usually unencapsulated, these lesions grow slowly, with intraglandular metastasis and local lymph node extension. In the late stages, it can spread to the lung. In older patients, chronic low-grade papillary carcinoma may rarely convert to an aggressive anaplastic carcinoma.
Treatment
Because papillary carcinoma retains the ability to synthesize thyroglobulin and to concentrate iodine in the early stages, radiation therapy is often effective. The initial treatment involves either partial thyroidectomy or total thyroidectomy with possible modified neck dissection (Figure 418).
Figure 418.
Algorithm for the management of papillary or follicular cancer. Tg, thyroglobulin; TSH, thyroid-stimulating hormone.
Surgical Measures
Patients can be classified as having either a low or a high risk for thyroid cancer based on their age, the size of the lesion, and evidence of extrathyroidal spread. Patients younger than 45 years of age who have lesions < 1 cm with no evidence of intra- and extrathyroidal involvement are considered to have a low risk for thyroid cancer. All other patients should be considered at high risk. For both low-risk and high-risk patients, total thyroidectomy is generally recommended, although a partial thyroidectomy may be adequate for the former group . If lymphatic spread is present on the initial evaluation, the patient should undergo a modified neck dissection as well; however, neck dissection is not indicated in the absence of lymphatic spread. In the hands of a skilled surgeon, thyroid surgery portends less than a 1% complication rate; the primary complications are hypoparathyroidism and recurrent laryngeal nerve damage. Immediately after surgery, the patient should be placed on suppressive T 4 therapy.
Postsurgical Measures
After undergoing a total thyroidectomy, patients should receive radioiodine to ablate the remnant thyroid bed to decrease the likelihood of recurrent disease. Radioablation also allows the physician to subsequently follow thyroglobulin levels as a marker for thyroid cancer activity.
The usual protocol requires thyroxine therapy to be stopped for 6 weeks and L -triiodothyronine (25 to 50 mcg) to be initiated for 4 weeks. The patient is then taken off all thyroid hormone therapy and goes on a low iodine diet for 2 weeks. This dietary modification allows for a rise in the patient's TSH level, which stimulates iodide uptake by the residual tumor. At maximal TSH stimulation (usually a TSH of > 50 U/mL), thyroglobulin is drawn and 25 mCi of 131 I is administered to the patient. The patient is scanned for residual radioactive iodine uptake 2472 hours later. An undetectable thyroglobulin level at a time when the serum TSH is elevated is the most sensitive test to determine that all thyroid tissue has been eradicated. If thyroglobulin is increased or radioactive iodine uptake is evident, a treatment dose of 131 I is given (see Figure 418).
The amount of 131 I given for the treatment of thyroid cancer depends on the degree of disease, the response to previous treatments , and the amounts of 131 I administered in the past. Approximately 3050 mCi of 131 I is used to ablate the thyroid remnant in a postsurgical patient who does not have metastatic disease; uptake is limited to the thyroid bed. For metastatic or recurrent disease, patients are generally treated with a 100200 mCi dose of 131 I. Side effects from doses larger than 100 mCi include sialadenitis, xerostomia, and temporary oligospermia. With cumulative doses of up to 300 mCi, no permanent sterility has been reported in women and < 10% of men have permanent sterility. Cumulative doses larger than 500 mCi have been associated with infertility, pancytopenia (in < 4.0% of cases), and leukemia (in 0.3% of cases). However, cumulative doses over 800 mCi have been associated with permanent sterility in up to 60% of women and 90% of men. A week after the treatment dose of 131 I, a post-treatment scan is performed. This scan is very useful in locating any subtle residual thyroid cancer that was not identified by the low-dose, pretreatment 131 I scan.
With postradioactive iodine treatment, the patient is placed on suppressive L -thyroxine therapy, with the goal TSH level ranging from below normal (< 0.1 mU/L) to undetectable. The patient is monitored at regular intervals, with either careful neck examination for new masses or lymphadenopathy with measurements of serum thyroglobulin, FT 4 , and TSH. Repeat radioactive iodine scans are performed at 12-month intervals with concomitant radioactive treatments as necessary. Once a negative scan and negative thyroglobulin are achieved at the time of elevated TSH, the patient may be followed up with a recombinant TSH radioactive scan instead of withdrawal from thyroid hormone therapy. Recombinant TSH allows the patient to avoid the discomfort of severe hypothyroidism and disrupting suppressive T 4 therapy. On the first 2 days, patients are injected intramuscularly with recombinant TSH. On the third day, a 35 mCi dose of 131 I is administered to the patient; on the fifth day, a whole-body scan is performed. TSH and thyroglobulin are measured on the third and fifth days. Because thyroglobulin is the most sensitive test for residual tumor, in some circumstances the uptake and scan can be deferred. The patient is likely to be free from disease if the serum thyroglobulin is < 1 ng/mL and the scan is negative. Thyroid cancer with a negative scan but a positive thyroglobulin positive thyroid level poses a diagnostic dilemma. As thyroid cancer dedifferentiates, it can potentially lose the ability to concentrate iodine and thus lose responsiveness to radioactive iodine treatment. Once excessive iodine intake is ruled out, patients generally undergo further imaging such as ultrasound, MRI, CT scanning, PET/CT scanning, or thallium or technetium-MIBI scanning to locate metastatic disease. If active thyroid disease is found, patients may undergo modified neck dissection to remove the metastatic disease.
Thyroglobulin antibodies in patient's serum can interfere with the thyroglobulin assay, and so the test is not reliable as a tumor marker. Under these circumstances, the patient may have to be followed with periodic imaging such as ultrasound or MRI.
Nonsurgical Measures
External radiation therapy may be useful in a variety of situations. Nonfunctional bone metastases respond well to external-beam therapy. Solitary metastatic lesions that do not concentrate radioactive iodine may respond to local external beam therapy. Brain metastases usually do not respond to 131 I and are best treated by either resection or gamma knife radiation therapy.
Prognosis
The overall prognosis of well-differentiated thyroid cancer is assessed by the initial staging and the adequacy of treatment. Table 415 describes the TNM staging system as well as 5- and 10-year survival rates. In this system, the staging is related to the age of the patient, recognizing that for patients who are younger than 45 years of age at the time of diagnosis, papillary tumors are relatively indolent. Stage 1 patients have an excellent 5-year survival rate of 99% and a 10-year survival rate of 98%.
Table 415. TNM Staging and Survival Rates for Adults with Appropriately Treated Differentiated Thyroid Carcinoma.
Stage
Description
5-year Survival Rate
10-year Survival Rate
1
Under 45: any T, any N, no M
Over 45: T < 1 cm, no N, no M
99%
98%
2
Under 45: any T, any N, any M
Over 45: T > 1 cm, no M, no M
99%
85%
3
Over 45: T beyond capsule , no N, no M
Or: any T, regional N, no M
95%
70%
4
Over 45: any T, any N, any M
80%
61%
The treatment modality, including the type of surgery, the radioactive treatment, and adequate L- thyroxine suppressive therapy, also affects the prognosis. Patients with tumors > 1 cm who receive partial thyroidectomies have a mortality rate that is 2.2 times greater than that of patients who undergo total thyroidectomies. Patients who have never undergone radioablation carry a twofold increased mortality rate at 10 years compared with patients who receive radioablation. Adequate suppressive therapy decreases the mortality rate but must be weighed against the possible side effects of tachycardia, arrhythmias, angina, and osteoporosis.
Follicular Carcinoma
General Considerations
Follicular carcinoma is the second most common thyroid cancer, accounting for 16% of all thyroid cancers.
Clinical Findings
Microscopically, follicular cancer forms small follicles that contain small, cuboidal cells with poor colloid formation. The distinction between carcinoma and adenoma requires the presence of capsular or vascular invasion. It is often difficult to distinguish a follicular carcinoma from a follicular adenoma on an FNA biopsy; therefore, a frozen section at the time of surgery is necessary. Like papillary carcinoma, follicular carcinoma retains the ability to synthesize thyroglobulin and concentrate iodine and is therefore responsive to radioactive iodine treatment. Rarely, follicular carcinoma synthesizes T 3 and T 4 and presents with hyperthyroidism and distant metastases. Follicular carcinoma tends to be slightly more aggressive than papillary carcinoma; it may spread to local lymph nodes or by the blood to bone or lung. Histologic variants, such as H
Print Close Window 
Ci of 123 I, radioactivity over the thyroid area is measured by scintigraphy at 4 or 6 hours and at 24 hours. The normal ranges of uptake vary with iodine intake. In areas of low iodine intake and endemic goiter, uptake may be as high as 6090%. In the United States, with a relatively high intake, the normal uptake is 515% at 6 hours, and 830% at 24 hours. 
1.0 cm or that have suspicious sonographic appearance proceed with FNA-guided ultrasound. Incidental thyroid nodules identified on positron emission tomography (PET) scans should undergo particularly careful evaluation because up to two thirds of these hypermetabolic lesions have been found to be cancers. 
