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Thyroid Disease: An Overview.

Thyroid disorders are very common. In the United States, more than 20 million people undergo treatment for a variety of thyroid diseases, and an estimated 2 million others have undiagnosed thyroid-related problems.[1]

The hallmarks of thyroid disorders vary. Some types of thyroid disease are due to the under- or overproduction of thyroid hormones. Disruptions in hormone synthesis often result in signs and symptoms that are subtle, diffuse and may be similar to other common medical conditions.

Gland enlargements -- goiters and nodules -- characterize other types of thyroid disorders. In these situations, the main concern is to differentiate between benign and malignant growth. Although altered hormone production also may be present, this ,sign does not confirm or refute a benign diagnosis. A pathologist must evaluate a fine-needle aspiration (FNA) biopsy or surgically removed thyroid tissue to confirm malignancy.

Epidemiological and demographic studies show that thyroid disorders are due to the intertwined effects of longevity, genetic predispositions, lifestyle factors and medical and environmental radiation exposures. Although using iodized salt is an easy way to prevent some forms of hypothyroidism, it is difficult or impossible to avoid other thyroid disease risk factors. Because a patient's age, family history of thyroid disease or previous exposure to radiation increases the possibility of malignancy, the patient history is an extremely important component of the examination.

Thyroid Gland Anatomy and Physiology

Anatomy

The thyroid gland is a butterfly-shaped organ located across the anterior surface of the trachea. A slender isthmus connects the 2 lobes, or wings, of the gland. (See Fig. 1.) Four parathyroid glands are embedded in the posterior thyroid surface.[2]

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The size of the gland varies and depends on heredity, environment and nutritional factors. On average, the normal thyroid weighs between 20 and 30 g and is approximately 2 to 2.5 cm in width and 3 to 5 cm in length.[3] Many thyroid abnormalities result in palpable and often visible gland enlargements.

Dark red in color, the thyroid gland is composed of thyroid follicles or thyroid secretory cells. The thyroid follicle cells surround a cavity where thyroglobulin, a product of follicle cell secretion, is stored. Thyroglobulin is a protein that is involved in the synthesis, storage and mobilization of iodine-containing thyroid hormones. The follicle cavity also contains a viscous colloidal protein.

In addition to thyroglobulin-secreting cells, a second population of cells lies between the follicle cells and the supporting basement membrane. The parafollicular cells or C (clear) cells produce the calcium-regulating calcitonin hormone. (See Fig. 2.)

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Physiology

The thyroid gland produces 2 fundamentally different classes of thyroid hormones: (1) the hormones thyroxine ([T.sub.4]) and triiodothryonine ([T.sub.3]) and (2) the small peptide hormone calcitonin. (See Table 1.) The [T.sub.4] and [T.sub.3] hormones are iodine-containing molecules that constitute the major secretory products of the thyroid gland. Because dietary iodine uptake is a unique thyroid-related function, clinicians can use radioactive iodine to:

* Assess thyroid size and position.

* Track hormone-secreting metastases.

* Ablate overactive or cancerous thyroid glands.
Table 1

Thyroid Hormones

Source             Hormone

Follicular         Thyroxine ([T.sub.4])
epithelium         Triiodothyronine ([T.sub.3])

Parafollicular     Calcitonin
cells (C cells)

Source             Target        Effects

Follicular         Entire body   Metabolism, oxygen
epithelium                       uptake, growth and
                                 development

Parafollicular     Bone,         Decreases calcium
cells (C cells)    kidneys       ion concentration in
                                 body fluids


To maintain physiologic homeostasis or balance, the synthesis and release of the [T.sub.4] and [T.sub.3] hormones is highly regulated. Thyrotropin-releasing hormone (TRH) from the hypothalamus and thyroid-stimulating hormone (TSH) from the anterior pituitary gland are molecules that regulate thyroid hormones by responding to [T.sub.4] and [T.sub.3] blood levels or to environmental stimuli.

Most of the secreted [T.sub.4] and [T.sub.3] is bound to serum proteins. The hormones are inactive in this form and circulate in the blood until needed. When needed physiologically, they are released from the serum proteins and move across plasma membranes and into the peripheral tissues. [T.sub.3], a [T.sub.4] conversion product, is the physiologically active hormone. In other words, physiological activity also regulates [T.sub.4] and [T.sub.3] synthesis, secretion and ultimately uptake by target tissues. (See Table 2.)
Table 2

Molecules Involved in the Regulation of [T.sub.4] and [T.sub.3]
Synthesis and Transport Into Peripheral Tissues

Molecule             Site of Origin         Target Site

Thyroid-releasing    Hypothalamus           Anterior pituitary
hormone (TRH)

Thyroglobulin        Thyroid                Thyroid

Thyroid-             Anterior pituitary     Thyroid
stimulating
hormone (TSH)

Albumin              Blood serum            [T.sub.4] and [T.sub.3]

Thyroid-binding      Blood serum            [T.sub.4] and [T.sub.3]
globulin

Thyroid-binding      Blood serum            [T.sub.4] and [T.sub.3]
prealbumin

Molecule             Regulation             Function

Thyroid-releasing    Exposure to cold       Controls TSH release
hormone (TRH)        and stress cause
                     increased TRH
                     production. This
                     causes TSH and
                     [T.sub.4] and
                     [T.sub.3] to
                     increase.

Thyroglobulin                               Synthesis of iodinated
                                            thyroid hormones

Thyroid-             High blood levels      [T.sub.4] and
stimulating          of [T.sub.4] and       [T.sub.3] release
hormone (TSH)        [T.sub.3] inhibit
                     TSH secretion

Albumin              Constitutive           Regulates the release
                                            of [T.sub.4] and
                                            [T.sub.3] into
                                            peripheral tissues

Thyroid-binding                             Same as above
globulin

Thyroid-binding                             Same as above
prealbumin


In addition to the [T.sub.4] and [T.sub.3] hormones, the thyroid gland produces calcitonin, the hormone responsible for the regulation of bone osteoclast and osteoblast activity and calcium blood levels. The parafollicular cells release calcitonin in response to elevated blood calcium.

Thyroid Hormones and Body Functions

Thyroid hormones are involved in a variety of important physiologic functions. The iodine-containing hormones, in one way or another, affect the body's entire physiology. Thyroxine and triiodothyronine influence the rate of protein and carbohydrate metabolism, oxygen consumption, electrolyte mobilization and carotene-to-vitamin A conversion. Thyroid hormones affect both neonatal central nervous system (CNS) development and reversible changes in adult CNS activity.

Calcitonin plays an equally important, though more easily defined, physiologic role. This hormone is one of several involved in maintaining homeostasis between the absorption of dietary calcium through the intestines, excretion of calcium by the kidneys and maintenance of calcium-dependent bone density.

Screening for Thyroid Abnormalities

Evaluating the thyroid gland is an essential part of a physical examination. The physician places his or her hands and fingers in various positions around the patient's neck and palpates the thyroid gland. Pushing the gland from side to side, the physician assesses its size, position and texture. (See Fig. 3.) The patient swallows, and as the gland moves, the clinician feels for nodules and other abnormal textures. Nodules that move with the thyroid gland are less of a concern than those fixed to the larynx or other neck structures.

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Based on the physical examination, the health care provider may request laboratory tests that include a thyroid profile, [T.sub.4] and TSH blood levels to determine euthyroid, hyperthyroid or hypothyroid status. A thyroid profile may include some of the following tests:

* [T.sub.3] uptake.

* Free [T.sub.4].

* Total [T.sub.4].

* Free thyroxine index.

* TSH[4].

However, enlarged or nodular thyroid glands, irrespective of their hormone-producing abilities, require further assessment.

Thyroid Pathology

Many thyroid gland pathologies are manifest by abnormal [T.sub.4] and [T.sub.3] blood levels. Causes of thyroid disease include low dietary iodine, environmental or medical radiation exposure and inherited disorders. However, there are many thyroid patients without known exposure or risk factors.

Hyperthyroidism

Hyperthyroidism, or elevated thyroid hormone blood levels, is caused by a diverse group of disorders. Excessive hormone production, in addition to originating from thyroid gland malfunction, also may be due to defects in the production of the TSH and TRH regulatory hormones. Some examples of pathologies associated with hyperthyroidism include:

* Anterior pituitary tumors.

* Toxic goiter or Graves disease.

* Hormone-producing thyroid tumors.

* Transient hyperthyroid conditions.

The signs and symptoms of hyperthyroid disease include heat intolerance, nervousness, personality change, weight loss, increased appetite, heart beat irregularities, excessive sweating and tremor. However, for geriatric patients the cause of these symptoms may be difficult to interpret in the context of other age-related conditions. Graves disease and other hyperthyroid-producing conditions disproportionally affect women. Laboratory tests used to evaluate hyperthyroidism assess:

* Anterior pituitary and TSH activity.

* Production and release of thyroid hormones.

* Production of thyroglobulin.

* Antithyroid antibodies.

The uptake of radioactive iodine, which shows the gland's ability to store and use the iodine needed to synthesize thyroxine and triiodothryonine, is another measure of the hyperthyroid condition. (See Table 3 and Fig. 4.)

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Table 3

Some Thyroid Laboratory Tests[4]

Name of Test          Normal Value (Adult)

Sensitive TSH         0.2-5.4 mU/L

Thyroglobulin         3-42 ng/mL

Total blood serum     5.4-11.5 [micro]/dL
   [T.sub.4]

Total blood serum     80-200 ng/dL
   [T.sub.3]

Free, unbound         0.7-2.0 ng/dL
   [T.sub.4]

Free, unbound         260-480 pg/dL
   [T.sub.3]

Radioactive iodine    1%-3% after 2 h;
uptake test           5%-20% after 6 h;
                      15%-40% after 24 h

Name of Test          Some Indications

Sensitive TSH         High - hypothyroidism
                      Low - hyperthyroidism

Thyroglobulin         High - metastatic thyroid cancer,
                         hyperthyroidism, some adenomas
                      Low -thyrotoxicosis

Total blood serum     High - hyperthyroidism, acute thyroidi-
   [T.sub.4]             tis
                      Low - hypothyroidism, hypoprotein-
                         emia, acute thyroiditis

Total blood serum     High - hyperthyroidism, acute thyroiditis
   [T.sub.3]          Low - acute thyroiditis

Free, unbound         High - Graves disease, euthyroid sick
   [T.sub.4]             syndrome
                      Low - primary hypothyroidism,
                        hypothyroidism due to pituitary or
                        hypothalamic pathology

Free, unbound         High - hyperthyroidism
   [T.sub.3]          Low - hypothyroidism due to thyroid or
                         pituitary pathology

Radioactive iodine    Increased uptake - hyperthyroidism
uptake test           Decreased uptake - hypothyroidism


Treatment of hyperthyroid conditions may require beta blockers to minimize cardiac complications, drugs to inhibit the synthesis of thyroid hormones, radioiodine ablation and surgery to reduce thyroid mass or to remove the gland. Intervention using beta blockers and thyroid-inhibiting drugs usually are temporary treatment methods. However, many patients receiving surgery or chemical ablation for their disease become hypothyroid and must take [T.sub.4] supplements.

Toxic Goiters

Goiters are chronic, noncancerous enlargements of the thyroid gland. Arising from various pathologies, hormone-producing goiters are called toxic goiters. Graves disease, the most common cause of noniatrogenic thyroid hormone excess, is an example of a toxic goiter.[5]

A diagnosis of hyperthyroidism requires both confirmation of hyperthyroid status and verification of the Graves disease condition. When patients present with classic symptoms -- hyperthyroidism, goiter and protruding eyeballs (exophthalmos) -- Graves disease is easily diagnosed. However, many patients with Graves disease do not manifest all 3 symptoms. Therefore, confirming the condition requires a thorough physical exam, appropriate laboratory tests and medical imaging procedures.

Graves disease patients usually have palpable, symmetric, smooth and nontender goiters. Tremor, as demonstrated by placing a sheet of paper on the patient's outstretched palms, is another physical indicator of Graves disease. Biochemical analysis reveals low TSH blood levels and markedly elevated [T.sub.4] values.[5] Without these landmark biochemical assessments, the signs and symptoms of Graves disease can be easily confused with:

* Anxiety neurosis.

* Pheochromocytoma.

* Menopause.

* Drug abuse or withdrawal.

* Myopathies.

* Other causes of hyperthyroidism.

Thyroid Storm

The descriptive term "thyroid storm" reflects a sudden and dangerous change in a patient's general health. Triggered by infection, trauma, surgery, diabetic acidosis, toxemia of pregnancy, discontinuance of antithyroid medication or fright, patients become feverish, restless, confused or psychotic and may progress to cardiovascular collapse and coma. Even with appropriate corrective and supportive medical treatment, the fatality rate is nearly 30%.[6]

Other Causes for Hyperthyroidism

Occasionally the thyroid gland is not the source of abnormally high thyroid hormone blood levels. When the thyroid gland is nonpalpable and [T.sub.4] and [T.sub.3] blood levels are high, the health care provider should consider other etiologies, such as TSH-producing pituitary adenomas and molar pregnancies, as the cause of hyperthyroid-appearing signs and symptoms.

TSH produced by the anterior pituitary gland regulates the production of the [T.sub.4] and [T.sub.3] hormones. Low hormone blood levels stimulate the production of TSH, and conversely, when hormone blood levels are high, TSH production diminishes. Although TSH-producing tumors are extremely rare, they cause hyperthyroidism due to the unregulated production of TSH hormone.

Molar pregnancies are an unusual and rare (1 in 1500 pregnancies) condition. Rather than producing a viable fetus, fertilization results in a hydatidiform mole, an intrauterine mass formed by partly developed products of conception.[7] The defective pregnancy, due either to the fertilization of an "empty egg" or to the abnormal replication of maternal genetic information, causes abnormal placental growth. Complete moles are composed entirely of placental tissue, while partial moles consist of a mixture of differentiated fetal and placental tissues.

Patients with complete molar pregnancies experience vaginal bleeding, nausea and vomiting. Ultrasound reveals a swollen placenta containing multiple cyst-like structures in the place of a fetus. (See Fig. 5.)

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Toxemia, a disease usually associated with the third trimester, can occur and uterine enlargement is advanced for the date of conception. Blood levels of human chorionic gonadotropin (hCG), a hormone used to mark the progression of a normal pregnancy, also are abnormally high.

After uterine evacuation, patients require hCG follow-up to monitor residual disease. Patients whose hCG levels plateau or do not return to nonpregnant levels (5.0 IU/L) must be assessed for choriocarcinoma, an invasive and malignant mole.[4,7]

About 1.4% of women with normal pregnancies and an equally small percentage of women with complete or invasive hydatidiform moles experience some signs and symptoms of hyperthyroidism. Although the thyroid gland is not enlarged and TSH blood levels are not elevated, these women demonstrate tremor, a fast heartbeat and an elevated body temperature. The reason for their apparent hyperthyroidism is molecular similarities between the hCG and TSH hormones. Similar to TSH's physiologic role, high hCG blood levels stimulate the synthesis [T.sub.4] and [T.sub.3]. Hyperthyroid symptoms subside when the pregnancy is completed, terminated or when invasive disease is treated.

Hypothyroidism

Impaired thyroid hormone production causes hypothyroidism. Reasons for impairment may be environmental, dietary, genetic or physiologic. (See Table 4.) The major causes of hypothyroidism are autoimmune disease, surgical removal or radioactive iodine ablation of the gland due to cancerous lesions, benign nodules or uncontrolled hyperthyroidism.
Table 4

Hypothyroidism Causes and Symptoms

Causes

Iodine deficiency
Drugs that inhibit thyroid hormone synthesis
Congenital hypothyroidism
Absence of thyroid gland
Pituitary insufficiency
Autoimmune disease

Symptoms

Decreased metabolic rate
Low body temperature
Cold intolerance
Cold, dry skin
Constipation
Coarse hair
Large thyroid


Other causes for hypothyroid disease include dietary iodine deficiency, metabolic disorders, congenital disease and the use of certain medications. Hypothyroid disease appears more frequently in white women (5-10:1) and most often occurs between 40 to 60 years of age.[8]

Hypothyroidism is a subtle, chronic and often slowly progressive endocrine-mediated disease. A detailed patient history, physical and diagnostic work-up is necessary because the signs and symptoms associated with hypothyroidism are diffuse, common to other medical problems and depend on the degree of hormonal insufficiency. Diagnosis of hypothyroid conditions requires astute clinical observation backed by laboratory testing. Tests used to confirm hypothyroidism include [T.sub.4], [T.sub.3] and TSH blood levels, blood electrolytes, blood glucose, alkaline phosphatase and various biochemical assessments of liver function.

Myxedema

The term myxdema usually describes severe or prolonged hypothyroidism. Myxedemic patients have changes in skin texture and facial appearance due to accumulation of hydrophilic mucopolysaccharides. The myxedemic patient has "doughy" skin, a puffy face and a large tongue. Affect (see glossary) is dull and the patient is lethargic, weak muscled and demonstrates sleep apnea. These patients usually are treated with oral doses of [T.sub.4], most of which is physiologically converted to [T.sub.3] before being taken up and used by target tissues. Untreated myxedema Progresses to myxedema coma.

Glossary of Terms

affect Facial expressions of mood and emotions.

autoantibody Antibodies made against host or "self" antigens.

autoimmune A response against "self" tissues,

autosomal An inheritance not affected by the sex chromosome.

congenital A condition existing at birth.

constituitive Always produced; nonregulated.

dominant A gene that is expressed in both the homozygous and heterozygous conditions.

endemic Always present in a community.

euthyroid A normally functioning thyroid.

gland A secretory organ.

histology Pertaining to the microscopic study of tissues.

hydatidiform A vesicular cyst.

hydrophilic Attracts water; water absorbing.

latency A period of apparent inactivity between a stimulus and the response.

iatrogenic An ill effect due to medical treatment.

mucopolysaccharides A molecule composed of a protein-polysaccharide complex.

osteoblast A bone-forming cell.

osteoclast A cell involved in the absorption and removal of bone.

sequester To concentrate or to separate.

sign An objective or measurable condition.

symptom A subjective and patient-reported sensation.

syndrome An aggregate of signs and symptoms associated with a particular disease.

Myxedema Coma

Myxedema coma is a rare, life-threatening condition that without medical intervention is nearly always fatal. It is precipitated by infection, medication or metabolic-related stress in hypothyroid-status patients. Patients with myxedema coma present with an altered mental status and a core temperature that may be as low as 29.5 [degrees] C (85.1 [degrees] F).[8] Other symptoms include abnormal heart rhythms, hypotension and respiratory disorders.

Treatment for myxedema coma, usually initiated in a hospital emergency room and continued in an intensive care facility, includes stabilizing acute respiratory failure, hypotension and hypothermia.

Emergency care physicians often are not aware of an incoming patient's thyroid disease history, and without readily available confirmatory laboratory tests, it is difficult to differentiate between myxedema coma and other similar presenting conditions. Therefore, the physician must rely on his or her "on-the-spot" clinical judgment to discriminate between myxedema coma and congestive heart failure, pulmonary edema, depression, septic shock or drug-induced toxicity. Even with optimal care, a 50% mortality rate is reported for this condition.[8]

Congenital Hypothyroidism

Congenital hypothyroidism affects the physical growth and mental development of babies and young children. Also known as cretinism, it may result from errors in thyroid hormone synthesis, anatomic abnormalities, iodine deficient diet or inadvertent in utero exposure to radioactive iodine.

Because maternal thyroid hormones pass through the placenta, most infants with congenital hypothyroidism look completely normal at birth. Relatively few are born with the classic cretin features that include a puffy face, flattened nasal bridge, protruding tongue, hoarse cry, protuberant abdomen and an umbilical hernia.

Treatment with supplemental thyroid hormones must begin within the first 6 weeks of birth to prevent permanent developmental problems. Epidemiological findings underscore the influence of the thyroid and the importance of neonatal screening programs to detect congenital hypothyroidism before the onset of permanent damage.

Endemic cretinism is a condition associated with developing countries where, because of poor diet and iodine-deficient soil and water, mothers and their babies are unable to produce iodine-containing thyroid hormones. Historically, these areas include certain parts of China, India and South America that are distant from the ocean, a source of naturally iodinated food and water. Unlike babies born with congenital cretinism, these babies are badly compromised at birth.

In its fully developed form, endemic cretinism is a devastating condition. Children with this condition are mentally retarded, deaf, unable to speak, of short stature and demonstrate rigidity of both the lower and upper extremities and the trunk.

Myxedematous cretinism is a more mild form of endemic (dietary) cretinism. These hypothyroid children, though less severely mentally compromised, are short and sexually underdeveloped. Similar to untreated hypothyroidism that occurs late in life, myxedemic children have thickened skin and facial features and dry, sparse body hair.

Nontoxic Goiters

A simple or nontoxic goiter is an enlargement of the thyroid gland not due to cancer or other types of organ disease. Unlike toxic goiters, they develop as a way for the body to compensate for a variety of hypothyroid-producing conditions, such as inadequate dietary iodine or excessive consumption of certain foods and drugs that decrease hormone synthesis. Some goitrogenic foods are cabbage, rutabagas, soybeans and peaches. Goitrogenic drugs include lithium and phenylbutazone.[9] Treatment for these goiters includes using iodized salt and limiting the consumption of goiter-producing substances.

Thyroiditis

Thyroiditis, or inflammation of the thyroid gland, can have an infectious or an autoimmune etiology. A frequent cause for thyroiditis is the immune system's inappropriate production of antithyroid antibodies. Autoimmune thyroiditis, also called Hashimoto thyroiditis, is the most common cause of primary hypothyroidism. Similar to other autoimmune diseases, Hashimoto thyroiditis is more prevalent in women than men and most commonly is diagnosed in people between the ages of 30 and 50.[10]

Interestingly enough, the incidence of Hashimoto thyroiditis is higher among those who have other autoimmune diseases such as lupus, diabetes, multiple sclerosis or rheumatoid arthritis. Women with insulin-dependent diabetes mellitus, rheumatoid arthritis, prematurely graying hair or loss of skin pigment, all of which have autoimmune components to their etiology, are at even greater risk (25%) for thyroid disease.[1]

On physical examination, Hashimoto thyroiditis reveals an enlarged, rubbery, nontender and nodular thyroid gland. Although it may first present as transient hyperthyroidism, this condition progresses to clinically evident hypothyroidism. Patients demonstrate a wide range of laboratory findings that include elevated TSH, low [T.sub.4], hypercholesterolemia and the presence of antithyroid autoantibodies. Treatment for autoimmune thyroiditis is [T.sub.4] replacement.

Thyroid Malignancies

Clinically detectable nodules occur in up to 4% of the population. (See Fig. 6.) Ultrasound will detect nodules in nearly 50% of people older than 60 years.[11] However, most nodules are not malignant. Thyroid malignancy accounts for only 1.5% of all new cancers and 0.2% of all cancer deaths.[12] Certain populations are at higher risk for thyroid cancer, including those who received:

* Prior neck irradiation for thyroid malignancy.

* Inadvertent environmental exposure to radioisotopes.

* Irradiation of the neck to treat other conditions. People with inherited multiple endocrine neoplasia (MEN) syndromes are at high risk for extremely virulent and invasive cancers.

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Other than the presence of thyroid nodules or gland swelling, thyroid cancer is not associated with distinctive signs or symptoms. Therefore, it is important to assess nodules for potential malignancy and initiate appropriate surveillance or treatment measures. Many types of thyroid cancer have 90% cure rates.[12]

Because thyroid malignancies are not necessarily associated with aberrant hormone profiles, other assessment methods are used to diagnose potential malignancy. These methods include fine-needle aspiration (FNA) biopsy, sometimes used in conjunction with high-resolution ultrasound and radioiodine uptake studies. Scintigraphy and other medical imaging methods are described later in this article.

FNA biopsy is an office-based and relatively noninvasive procedure. The physician administers a local anesthetic and instructs the patient not to move, cough, swallow or talk. Although not a painful procedure, the patient feels pressure. The clinician aspirates superficial or palpable lesions without guidance. However, needle placement for nonpalpable lesions requires ultrasound assistance. (See Fig. 7.)

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When the properly positioned needle plunger is retracted, it aspirates cells and sometimes liquid into the syringe. The clinician moves the needle up and down and sometimes at different angles to assure collecting a relevant and representative sample. Collected aspirate is expressed onto a glass slide and into a fixative-containing test tube.

The material on the glass slide is immediately fixed using 95% ethanol or a commercially prepared spray fixative. Slides may be inspected at the point of service to avoid collection of a nondiagnostic sample. The procedure may have to be repeated many times. Afterwards, the patient may experience local soreness and bruising. The FNA often can differentiate benign and malignant tumors and diagnose papillary, follicular, medullary and anaplastic cancers.

Papillary Cancer

Papillary thyroid cancers are the most frequently encountered (80% to 90%) and curable forms of the disease. (See Table 5.) Papillary carcinoma typically appears as an irregular-shaped, solid or cystic mass arising from otherwise normal thyroid tissue. Epidemiologists associate previous radiation exposure with an increased risk for this type of thyroid carcinoma. This includes patients who received radiation to treat other cancers and, as was popular in the 1940s and 1950s, to shrink swollen tonsils and adenoids. Epidemiological and demographic data from the 1986 Chernobyl nuclear accident also confirm the link between radiation exposure and papillary thyroid carcinoma. (See Fig. 8.)

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Table 5

Some Thyroid Cancer Characteristics

Type          Peak Onset    Prominence        Risk Factors

Papillary     30-50 y       3:1,              Prior radiation
                            women:men         exposure

Follicular    40-60 y       3:1,              Unknown
                            women:men

Medullary     Sporadic -    Sporadic - 3:2,   Inherited syn-
              40-60 y       women:men         drome; unknown
              MEN 2A -      MEN 2A, MEN       environmental
              mid 30s       2B - 1:1,         factors
                            women:men

Anaplastic    >65 y         2:1,              Neck irradiation
                            men:women

Type          Characteristics             Prognosis

Papillary     Commonly spreads            Excellent
              to neck lymph               prognosis
              nodes; metastases
              to lung or bone
              uncommon

Follicular    Invades veins and           Good prognosis
              arteries within thy-        for tumors <1
              roid gland; occa-           cm
              sional spread to
              lung and bone;
              spread to lymph
              nodes uncommon

Medullary     Early spread to             Poor prognosis
              neck lymph nodes;           for men, >50 y,
              late spread to dis-         metastases,
              tant organs                 MEN 2B

Anaplastic    Rapidly growing             Poor prognosis
              neck mass; typical-
              ly spreads to neck
              lymph nodes and to
              distant sites

MEN 2A indicates multiple endocrine neoplasia syndrome, type 2A; MEN
2B - multiple endocrine neoplasia syndrome, type 2B


Because of its relatively nonvirulent and noninvasive nature, 10-year survival rates for all patients with papillary thyroid cancer are estimated to be 80% to 95%.[13] Although fortunate, high survival rates produce a certain amount of controversy concerning treatment and management of this particular cancer. Some surgeons believe that removing the tumor-containing portion of the thyroid is sufficient, while other surgeons argue that a total thyroidectomy is the most appropriate treatment for this disease.

Follicular Cancer

Follicular thyroid cancer is the second most common thyroid cancer, accounting for 10% to 15% of cases, and it is not associated with previous radiation exposure. Arising from thyroidal follicle cells, this malignancy is somewhat more aggressive, with cure rates depending on the size of the tumor, the patient's age and spread to distant sites. As with papillary cancer, there is discussion concerning the role of total thyroidectomy in treatment. However, postoperative treatment with iodine 131 and thyroid hormone replacement therapy is central to a long-term cure for both papillary and follicular tumors.[13]

Medullary Cancer

The parafollicular cells or C (clear) cells are the source of medullary cancer. Because the C cells produce calcitonin, this cancer is neither affected by thyroid-regulating hormones nor does it affect thyroid hormone synthesis. The incidence of medullary cancer ranges from 5% to 8% of diagnosed thyroid malignancies.

Medullary thyroid cancer can occur sporadically, or it can result from one of 2 inherited MEN syndromes. Sporadic medullary cancer, which arises from unknown risk factors, accounts for the majority of cases and generally has a poor prognosis. Prognosis is further compromised if the patient is male and older than 50 years.[13]

Medullary cancer caused by MEN syndrome is an inherited autosomal dominant disease that affects men and women equally. MEN, type 2A is a group of endocrine disorders that includes bilateral medullary carcinoma, pheochromocytoma and hyperparathyroidism. Patients with MEN, type 2B, in addition to having bilateral medullary carcinoma and pheochromocytoma, demonstrate mucosal tumors and multiple skeletal and cardiovascular abnormalities.

Patients with medullary cancer receive total thyroidectomies and complete removal of all central neck lymph nodes and fatty tissues. Because these cells do not make iodine-containing hormones, iodine-based treatments are not effective. However, serum calcitonin, a C cell-specific product, is an effective way to monitor treatment efficacy.

Anaplastic Cancer

Anaplastic tumors are the least common (2% to 3%) and the most deadly thyroid cancers. Even with aggressive treatment, only 10% of these patients live 3 years after diagnosis. These cancers arise in more differentiated thyroid cancers or in benign goiters. Like papillary cancer, anaplastic tumors are linked to previous radiation exposure. They grow rapidly and at time of diagnosis have already metastasized to the lymph nodes, trachea and lungs. Due to invasive spread to vital neck structures, most anaplastic tumors are inoperable at the time of diagnosis, and thyroidectomy is possible only for a few patients. Some patients benefit from combined radiation and chemotherapy protocols.

Preventing Thyroid Disease

Epidemiological and demographic studies allow scientists and clinicians to recognize genetic, environmental, medical and lifestyle influences on the potential for thyroid pathologies. Some genetic predispositions, such as MEN syndromes, are not preventable in people who carry the MEN gene cluster. However, clinicians can provide genetic advice and vigilant medical care to affected patients and their families. In addition, lifestyle and environmental factors also modify the affects of genetics on disease incidence.

Increases in thyroid cancer are clearly linked to ionizing radiation exposure, although avoiding medically necessary or accidental exposure is not always possible. The effect of diet on thyroid disease is clear-cut and easily modified. People who do not consume enough dietary iodine cannot make thyroid hormones.

Diet

Iodine, a naturally occurring constituent of soil and water, is a required dietary nutrient. Normally, humans get enough iodine in their diets by eating fish or vegetables and drinking milk and water that contain this water-soluble element. However, goiter results when the recommended daily allowance of 0.14 mg of iodine is not met on a consistent basis.[14] Goiter and cretinism are common in the Himalayas and Andes, where in addition to low levels of naturally occurring iodine, overall health is compromised by poverty.

The Great Lakes basin of the United States is another geologically iodine-deficient area. However, based on research conducted during the first quarter of the 20th century, goiter is prevented in these regions by using iodized salt.[15]

In the United States, the use of iodized salt has nearly eliminated endemic goiter and cretinism. According to the Salt Institute, nearly half of the table salt sold in the United States contains supplemental potassium iodide or cuprous iodide. In spite of this simple remedy, iodine deficiency remains a major world health problem. When associated with mental retardation and cretinism, iodine deficiency causes an estimated 10% to 15% reduction in an affected population's overall IQ.[15]

Medical Radiation Exposure

Prior head and neck irradiation for thyroid and non-thyroid-related illnesses is a risk factor associated with increased frequency of papillary and anaplastic thyroid cancers. The time from the first radiation exposure to the discovery of a thyroid cancer (latency period) is about 10 years for children and 20 years for adults.[16] Although radiation to treat primary and metastatic malignancies is necessary and extends quality of life, irradiation for other purposes should be avoided.

In the past, low-dose radiation to the neck was used for reasons that sound foolish today. For example, because an enlarged thymus was thought to cause sudden infant death syndrome (SIDS), many infants were treated with radiation to shrink the thymus gland. Radiation also was used to shrink tonsils, adenoids and to treat adolescent acne.[16] This practice stopped in 1955 when researchers at the University of Chicago discovered the link between childhood irradiation and the eventual development of thyroid cancer.

Environmental Radiation Exposure

Exposure to environmental sources of iodine 131 ([sup.131]I) through radioactive fallout or nuclear accidents is associated with increased incidence of thyroid cancer. In a recent National Cancer Institute (NCI) study,[17] epidemiologists demonstrated that aboveground nuclear tests of the 1950s exposed Americans to varying levels of iodine 131, with exposure depending on the person's age and diet. Because radioactive fallout is carried by wind and rain until eventually it is deposited on surface waters and grazing fields, consumption of milk is a particularly important variable. The NCI study reported that more than 150 million Americans have been exposed to radioactive fallout, and epidemiologists estimate their overall iodine 131 dose to be between 1 and 4 rads (0.01 to 0.04 Gy). Although the effects are difficult to prove, children of the 1950s bear added risks for thyroid and other radiation-associated cancers.

Studies of the Chernobyl explosion on April 26, 1986 also link iodine 131 exposure to incidences of thyroid cancer. According to Vasily S. Kazakov of the Belarus Ministry of Health in Minsk, pediatric thyroid cancer cases began to soar in 1990. Scientists were surprised to find that in addition to young children, iodine 131 exposure affected those who were still in the womb when the Chernobyl accident occurred.[18] The latency period for Chernobyl-induced thyroid cancer is approximately 4 years.

Using the World Health Organization tumor classification system, most of the Chernobyl cancers are papillary carcinomas. However, unlike other radiation-associated papillary tumors, these are more aggressive and frequently invade the parathyroids and surrounding lymph nodes and demonstrate distant lung metastases.

Medical Imaging of Thyroid Disease

Commonly used medical imaging methods, though not usually diagnostic, play an important role in locating and evaluating thyroid nodules and other thyroid abnormalities.

Thyroid Scintigraphy

Because [T.sub.4] and [T.sub.3] hormones contain iodine molecules, they provide the mechanism for organ-specific scintigraphic imaging. Thyroid scans initially used [sup.131]I, but imaging now is performed using technetium Tc 99m ([sup.99m]Tc) or iodine 123 ([sup.123]I).[19] Because it emits both gamma and tissue-damaging beta radiation, [sup.131]I is limited to thyroid gland ablations and thyroid cancer treatment. (See Fig. 9.)

[ILLUSTRATION OMITTED]

Most radiologists consider [sup.123]I the isotope of choice because of its short half-life and emission of pure gamma energy. However, there is some question about the merits of using [sup.99m]Tc for scintigraphic imaging. Although the thyroid gland sequesters [sup.99m]Tc, the isotope is not incorporated into [T.sub.4] and [T.sub.3] molecules. Therefore, [sup.99m]Tc scintigraphy only provides anatomical information.[20]

Iodine 123 scintigraphy typically is used to:

* Identify and evaluate nodules.

* Assesses thyrotoxicosis.

* Locate abnormal thyroid tissue.

Iodine 123 distribution and the identification of hot (increased [sup.123]I uptake) and cold (depressed [sup.123]I uptake) nodules indicate specific pathologies. Taken in concert with the patient's history and related lab work, areas of diffuse and increased uptake are associated with hyperthyroidism and Graves disease, while areas of diffuse or mottled and decreased [sup.123]I uptake are associated with hypothyroidism and Hashimoto thyroiditis. Some cold, nonfunctioning nodules are cancerous.[4] (See Fig. 10.)

[ILLUSTRATION OMITTED]

Ultrasound

Though not a malignancy-defining procedure, thyroid ultrasound provides information concerning the size, number and location of thyroid nodules. In addition to these physical parameters, ultrasound demonstrates other subtle lesion characteristics such as nodule perimeters, calcifications and the presence of blood or other fluids in nonsolid nodules. Some of these characteristics are associated with malignancy.

Ultrasound recognizes nodules missed on physical examination and by scintigraphy, CT and MR studies. Small nodules (2 to 3 mm) are identified easily.[19] However, as stated before, in spite of the high sensitivity of this method, ultrasound does not identify malignancy.

Ultrasound characteristics that suggest a benign nodule include:

* A well-circumscribed nodule or nodule halo. (See Fig. 11.)

* A fluid-filled nodule.

* Multiple nodules.

* No blood flow to the nodule.

* Adenoma-associated calcifications.

[ILLUSTRATION OMITTED]

Ultrasound in combination with FNA is a powerful method to assess nodules for malignancy.

Computed Tomography and Magnetic Resonance Imaging

Although both CT and MR can provide detailed thyroid images (see Fig. 12), neither method detects nodules as well as high-resolution ultrasound.[19] Both methods are more expensive than ultrasound. In addition, CT exposes patients to radiation and to iodine-containing contrast media. The latter issue may cause delays in the use of [sup.123]I for scintigraphic imaging or [sup.131]I for cancer treatment.

[ILLUSTRATION OMITTED]

MR is affected by motion due to swallowing, breathing and vascular pulsation. However, it is effective in evaluating substernal goiters and in determining the degree of tracheal obstruction caused by these goiters.[20]

Safety

The use of radioisotopes for treatment or imaging presents safety issues that not only affect patients, their families and caretakers but also can adversely affect the environment. The International Commission on Radiation Protection (ICRP) introduced the "as low as reasonably achievable" (ALARA) concept.[21] Applied to both patients and personnel, the 3 basic ALARA tenets are:

* No practice involving radiation exposure shall be adopted unless its introduction produces a net positive benefit.

* All radiation exposures shall be kept as low as reasonably achievable, taking into account economic and social factors.

* The dose equivalent to individuals shall not exceed recommended dose limits for the appropriate circumstances.

The major concern in thyroid imaging and treatment is safe handling and use of radioactive iodine and [sup.99m]Tc.

Iodine 123 (half-life of 13 hours) and [sup.99m]Tc (half-life of 6 hours) are relatively short-lived, gamma-emitting isotopes. Therefore, their safe handling is less complex than the practices needed for the safe handling of the beta-emitting isotope [sup.131]I (half-life of 8 days). However, in either situation, hospital personnel, patients and their families must understand specific precautions:

* Patients may need to be isolated.

* Exposure to pregnant and lactating women should be avoided.

* Care should be taken in record keeping.

* Family must reduce their exposure by distance and personal contact measures.

* Health care personnel must reduce their exposure by distance, shielding and other facility-mandated protection measures.

Of the 3 isotopes used in imaging or treating thyroid disease, [sup.131]I has the greatest potential for environmental harm. Damage at the molecular level includes alteration of key proteins and enzymes, damage to structural and functional lipids and interference with DNA replication processes.

Conclusion

Thyroid disorders are commonly encountered in the general population. Diagnosing specific thyroid diseases depends on physical exam findings and the interpretation of laboratory and medical imaging results. Although thyroid goiters and nodules are a common finding, most of these growths are benign. Differentiating between benign and malignant thyroid disease is a challenging task that requires the skills and expertise of many different health care professionals.

Thyroid Disease: An Overview

To receive Category A continuing education credit for this Directed Reading, read the preceding article and circle the correct response to each statement. Choose the answer that is most correct based on the text. Transfer your responses to the answer sheet on Page 66 and then follow the directions for submitting the answer sheet to the American Society of Radiologic Technologists. You also may take Directed Reading quizzes online at www.asrt.org.
1. The thyroid gland produces:

   a. calcitonin.
   b. TRH and TSH.
   c. [T.sub.4] and [T.sub.3].
   d. A and C.

2. Thyroid hormones are unique because they
   contain:

   a. protein.
   b. iodine.
   c. nitrogen.
   d. calcium.

3. The production of thyroid hormones ultimately is
   regulated by:

   a. changes in body temperature.
   b. the hypothalamus and anterior pituitary glands.
   c. blood calcium levels.
   d. parathyroid glands.

4. Which of the following physiologic functions is not
   directly affected by thyroid hormones?

   a. protein and carbohydrate metabolism.
   b. red blood cell production.
   c. central nervous system development.
   d. bone density maintenance.

5. While inspecting the thyroid gland, physicians ask
   patients to swallow to:

   a. evaluate the swallow reflex.
   b. feel for lymph node metastases.
   c. evaluate the larynx.
   d. feel for nodules and other abnormal textures.

6. Based on clinical exam findings, a physician may
   recommend:

   a. [T.sub.4] and TSH blood level tests.
   b. a blood count.
   c. a glucose tolerance test.
   d. evaluation of the patient's diet.

7. Symptoms of hyperthyroidism include:

   a. cold intolerance and high blood pressure.
   b. weight gain and low blood pressure.
   c. anti-thyroid antibodies and low blood iodine.
   d. heat intolerance and nervousness.

8. Treatment for hyperthyroidism includes:

   a. supplemental iodine.
   b. radioiodine ablation and surgery.
   c. supplemental [T.sub.4] and [T.sub.3].
   d. anterior pituitary removal.

9. A patient with a palpable smooth goiter, tremor
   and low TSH is likely to have:

   a. Graves disease.
   b. Hashimoto thyroiditis.
   c. endemic goiter.
   d. papillary cancer.

10. A patient with symptoms of hyperthyroidism is likely to have:

    a. low TSH.
    b. high TSH.
    c. low serum [T.sub.4].
    d. decreased iodine uptake.

11. The signs and symptoms of menopause, drug
    abuse and anxiety are easily confused with:

    a. thyroid storm.
    b. myxedema.
    c. molar pregnancy.
    d. Graves disease.

12. Two life-threatening thyroid conditions are:

    a. Graves disease and myxedema.
    b. hyperthyroidism and hypothyroidism.
    c. adenoma and papillary cancer.
    d. thyroid storm and myxedema coma.

13. Human chorionic gonadotropin can:

    a. mimic TSH.
    b. induce molar pregnancies.
    c. inhibit [T.sub.4] and [T.sub.3] production.
    d. lower blood pressure.

14. Endemic cretinism is due to:

    a. a protein-deficient diet.
    b. inherited disease.
    c. iodine-deficient diet.
    d. inability to produce thyroid-binding serum
       proteins.

15. An enlargement of the thyroid gland not due to
    cancer or other disease processes is:

    a. a simple goiter.
    b. a papillary nodule.
    c. Hashimoto's thyroiditis.
    d. medullary thyroiditis.

16. A risk factor for Hashimoto thyroiditis is:

    a. young age.
    b. having diabetes or rheumatoid arthritis.
    c. high dietary iodine.
    d. being underweight.

17. Thyroid nodules:

    a. occur rarely.
    b. are usually malignant.
    c. are usually palpable.
    d. are common.

18. The purpose of using ultrasound guidance for a
    fine-needle aspiration is to:

    a. reduce bruising.
    b. collect cells from large palpable nodules.
    c. collect cells from nonpalpable nodules.
    d. destroy the nodule.

19. Which of the following is a risk factor for papillary
    cancer?

    a. prior radiation exposure.
    b. metastases to lymph nodes.
    c. use of birth control pills.
    d. rheumatoid arthritis.

20. Which thyroid cancers have the highest cure rates?

    a. medullary and anaplastic cancers.
    b. adenomas and anaplastic cancers.
    c. medullary and MEN-associated cancers.
    d. papillary and follicular cancers.

21. Iodine 131 is not an effective treatment for:

    a. papillary cancer.
    b. follicular cancer.
    c. medullary cancer.
    d. follicular metastases.

22. The reason for the answer to question 21 is:

    a. papillary cancer is too aggressive.
    b. metastases grow too fast.
    c. medullary cells do not produce iodine-containing
       hormones.
    d. most thyroid cancers do not produce iodine-containing
       hormones.

23. On iodine 123 scintigraphy, areas of diffuse and
    increased uptake are likely to be:

    a. cancer.
    b. hypothyroidism.
    c. Hashimoto thyroiditis.
    d. Graves disease.

24. Which sonographic characteristic suggests a
    benign nodule?

    a. poorly-defined margins.
    b. a single nodule.
    c. no fluid inside nodule.
    d. adenoma-associated calcifications.

25. Magnetic resonance imaging of the thyroid:

    a. is less expensive than an ultrasound exam.
    b. detects nodules better than ultrasound.
    c. can be affected by motion due to swallowing or

       breathing.
    d. may cause delays in scintigraphic imaging if
       iodine-containing contrast media are used.

Reference No. DRI0001011


DRI0001011

Expiration Date: Oct. 31, 2003 (*)

Approved for 1.5 Cat. A CE credits

(*) Your answer sheet for this Directed Reading must be received in the ASRT office on or before this date.

References

[1.] Thyroid disorders overview. Available at: http://cmpcnet.columbia.edu/dept/thyroid/disorders.html. Accessed October 15, 2000.

[2.] Seely R, Stephens T, Tate P. Anatomy and Physiology. 3rd ed. New York, NY: Mosby; 1995.

[3.] Straub W. Manual of Diagnostic Imaging. 2nd ed. Boston, Mass: Little Brown; 1989.

[4.] Fischbach F. A Manual of Laboratory and Diagnostic Tests. 6th ed. Philadelphia, Pa: Lippincott; 2000.

[5.] The many faces of Graves' disease. Available at: http://www.postgradmed.com/issues/1999/10_15_ 99/felz.htm. Accessed May 15, 2001.

[6.] Symptoms and thyroid storm. Available at: http://daisyelaine_co.tripod.com/gravesdisease/id1 .hrml. Accessed May 15, 2001.

[7.] Molar pregnancy. Available at: http://www.hygeia .org/poems11.htm. Accessed May 30, 2001.

[8.] Hypothyroidism and myxedema coma. Available at: http://www.emedicine.com/EMERG/topic280.htm. Accessed May 13, 2001.

[9.] Available at: http://www.nlm.nih.gov/medlineplus /ency/article/00179.htm. Accessed May 15, 2001.

[10.] Thyroid disorders. Available at: http://www .execpcpc.com~shaws/nursing/Thyroid.txt. Accessed May 13, 2001.

[11.] Evaluation of the thyroid nodule. Available at: http://www.medscape.com/moffitt/CancerControl/2000/v07.n03/cc0703.01. mcca/pnt-cc07. Accessed April 14, 2001.

[12.] An introduction to thyroid disease. Available at: http://thyroid.about.com/health/thyroid/library/ weekly/aa051800a.htm. Accessed May 31, 2001.

[13.] Thyroid cancer. Available at: http://www .endocrineweb.com. Accessed May 15, 2001.

[14.] Audesirk T, Audesirk G. Biology: Life on Earth. 4th ed. Upper Falls River, NJ: Prentice Hall; 1996.

[15.] Iodized salt. Available at: http://www.saltinstitute .org/37.html. Accessed June 6, 2001.

[16.] Current concepts in the management of thyroid cancer. Contemp Surg. 2000;56(1):40-52.

[17.] National Cancer Institute study estimating thyroiddoses of I-131 received by Americans from the Nevada atmospheric bomb test. Available at: http://rex .nci.nih.gov/massmedia/exesum.html. Accessed: June 7, 2001.

[18.] Correspondence - thyroid cancer after Chernobyl. Available at: http://www.ratical.org/radiation/inetSeries/ChernyThyrd.html. Accessed April 24, 2001.

[19.] Baskin HJ, ed. Thyroid Ultrasound and Ultrasound-Guided FNA Biopsy. Boston, Mass: Kluwer Academic Publishers; 2000.

[20.] Sandler MP, Patton J, Gross M, Shapiro B, Falke T, eds. Endocrine Imaging. Norwalk, Conn: Appelton and Lange; 1992.

[21.] Thompson MA, Hattaway MP, Hall JD, Dowd SB. Principles of Imaging Science and Protection. Philadelphia, Pa: WB Saunders Co; 1994.

Janet Yagoda Shagam, Ph.D., is a microbiologist with more than 25 years of experience teaching college-level biology, medical and environmental microbiology and chemistry. In addition, she is actively engaged in field and laboratory-based microbiology research and medical photography.

Dr. Yagoda Shagam, an award-winning medical and science writer, has written numerous professional articles, peer-reviewed research articles, case studies for BioQuest and made presentation to various clinical, community, national and international professional organizations. Dr. Yagoda Shagam serves on several editorial boards and is the Southwest regional director for the American Medical Writer's Association.

The author thanks Kathleen Colleran, M.D., assistant professor of medicine and endocrinology, University of New Mexico in Albuquerque, for providing the opportunity to observe many of the procedures described in this Directed Reading and for reviewing the final manuscript.

Thanks also to Liana Watson, B.A., R.T.(R)(M)(S), RDMS, RVT, of Regional West Medical Center in Scottsbluff, Neb, for the ultrasound, CT and scintigraphic images used to illustrate the text.

Reprint requests may be sent to the American Society of Radiologic Technologists, Communications Department, 15000 Central Ave. SE, Albuquerque, NM 87123-3917.

[C] 2001 American Society of Radiologic Technologists.
COPYRIGHT 2001 American Society of Radiologic Technologists
No portion of this article can be reproduced without the express written permission from the copyright holder.
Copyright 2001 Gale, Cengage Learning. All rights reserved.

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Publication:Radiologic Technology
Geographic Code:1USA
Date:Sep 1, 2001
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