Thyroid

Physiology

The main function of the thyroid gland is to synthesize thyroid hormone: thy-roxine (T4) and 3,5,3'-triiodothyronine (T,). These hormones require iodine for synthesis. Thyroid tissue is good at trapping iodine.

Circulating T₄ is predominantly bound to thyroxin-binding globulin (TBG). T₄ is deiodinated in peripheral tissues to the more bioactive T₃. The free thyroid hormones bind to specific receptors in the cell, leading to increases in oxygen consumption, stimulation of protein synthesis and increases in metabolism.

Secretion of thyroid hormones is regulated by TSH which is produced and secreted by the anterior pituitary gland. TSH synthesis and release are stimulated by thyroid-releasing hormone (TRH), which is synthesized in the hypothalamus and secreted into the pituitary. T₄ and T₃ inhibit the action of TRH on the anterior pituitary, thereby decreasing the secretion of TSH.

Thyroglobulin is a glycoprotein which, under normal conditions, is barely detectable in plasma. Thyroglobulin is found at higher concentrations in plasma under such conditions as subacute thyroiditis, radiation therapy, and goiter. Serum thyroglobulin levels can also be used to detect recurrent or persistent cases of thyroid cancers.

Free T₄ and TSH are the most commonly useful tests in pediatric thyroid disorders, but test results should always be interpreted in conjunction with the child's overall clinical condition. T₃ levels usually only need to be measured when a patient is suspected of having hyperthyroidism but has normal T₄ levels.

Serum thyroid antibodies are frequently elevated in autoimmune thyroid diseases. Approximately 80% of patients with Hashimoto's disease have elevated antimicrosomal autoantibodies, and most patients with Graves' disease have detectable thyroid-stimulating immunoglobulins. The presence of these antibodies does not determine the functional status of the thyroid, but they are helpful in the diagnosis of autoimmune thyroid disorders.

Thyroid Problems

In North America, the most common cause of hypothyroidism in children older than 6 years of age is Hashimoto's disease (chronic lymphocytic thyroiditis). This disorder is considered to be an autoimmune disease, and most patients have high levels of antimicrosomal and antithyroglobulin antibodies. The disease usually presents as an asymptomatic, slowly growing goiter. However, patients can have decreased or increased levels of thyroid hormone, although many are normal. Treatment with thyroid hormone usually results in regression of the goiter. Thyroid surgery may be indicated in cases of goiter that do not respond to medical therapy, if the goiter is causing airway problems, or if malignancy in a nodule cannot be ruled out.

Goiter

Although the widespread use of iodine in food processing and salt has virtually eliminated the occurrence of goiter due to iodine deficiency in the United States, the prevalance of this disorder has remained high in many portions of the Developing World. Even worse, the effect of iodine deficiency on the brain function of the developing fetus or newborn child has remained unchanged over the past 20 years. Thus, cretinism and its associated diseases remain a world health problem. Sporadic goiter still occurs in children in the United States for reasons that are poorly understood, and can be treated with thyroid hormone.

Hyperthyroidism

Hyperthyroidism (or thyrotoxicosis) is associated with an excess of thyroid hormones. The predominant cause of hyperthyroidism in children, as in adults, is Graves' disease. The disorder in children accounts for 1% to 5% of all patients with Graves' disease, 10% to 15% of all pediatric thyroid disorders, and approximately 30% of all goiters in children. The disorder is rare in children younger than 3 years of age and increases progressively with age thereafter.

Graves' Disease

Graves' disease is an autoimmune disease results from thyroid-stimulating immunoglobulins and other antibodies. Graves' disease includes goiter (virtually 100%), thyrotoxicosis (hyperthyroidism), exopthalmus (bulging eyes), and pretibial myxedema (leg swelling). The systemic manifestations of thyrotoxicosis include heat intolerance, thirst, increased appetite, weight loss, sweating, palpitations, tremor, and emotional liability. Severe eye disease and pretibial myxedema are rare in children.

The diagnosis of Graves' disease is confirmed by elevated T₄ or T, levels associated with a goiter (enlarged thyroid). Thyroid scans are usually unnecessary but show diffuse, rapid uptake of ₁₂₃I or _99mTc; this characteristic differentiates Graves' disease from Hashimoto's disease or toxic nodular goiter.

Treatment of Graves' disease should be highly individualized based on age, the family's preference, the severity of disease, the size of the goiter, and bv the response to initial treatment. The options include therapy with and thyroid drugs, radioactive iodine, and thyroidectomy. Most patients with childhood Graves' disease are treated with the antithyroid drugs propylthiouracil (PTU) or methimazole. The average period from onset of therapy to having normal thyroid levels is 8 weeks, and the drugs may have to be continued for 2 to 4 years until patients undergo spontaneous remission. Antithyroid drug therapy is often combined with a B-blocking agent to initially control the acute symptoms. The disappearance of the goiter has been found to be indicative of spontaneous remission. One quarter to one third of patients initially treated with antithyroid drugs are eventually treated with radioactive iodine or surgery. Drug toxicity may occur in up to 15% of patients. Minor reactions include skin rash and itching without rash. More serious complications include low white blood cell count, low platelet count, severe skin effects, and liver dysfunction.

Surgical or radioactive iodine (₁₃₁I) treatments are needed for patients in whom antithyroid drug therapy has failed. Because of the long life expectancy of children and the long term radiation effects, reluctance to use radioactive iodine as a first-line therapy in young children is understandable. However, no studies document chromosome abnormalities or increased cancer after treatment with radioactive iodine. In preadolescent children ₁₃₁I is still used on a case-by-case basis. Because of its low cost and ease of use, ₁₃₁I has become the preferred treatment alternative after antithyroid drugs in older adolescents and adults. The risk for recurrence with an initial response to ₁₃₁I is less than 5%, but several months or more are needed before hyperthyroidism is controlled. About 70% of patients treated develop hypothyroidism within 10 years of treatment.

Surgical treatment of Graves' disease offers rapid and permanent alleviation. Preparation for thyroidectomy with medical therapy can be accomplished within 6 weeks using antithyroid medications, and if necessary, within 1 week using B-blocking agents. Iodine may also be used 2 weeks before the operation to achieve thyroid control if B-blocking agents are contraindicated. Patients prepared with propranolol alone must have the drug continued for 5 to 7 days after surgery to prevent thyroid storm because the circulating half-life of thyroxin is approximately 7 days. Thryoidectomy for Graves' disease is a safe procedure with minimal risk of vocal cord paralysis or permanent hypoparathyroidism.

The appropriate extent of thyroidectomy for Graves' disease remains controversial. The traditional approach is bilateral near-total thyroidectomy. The problems with this approach include determining how much of a remnant should remain and the risk for recurrent hyperthyroidism. Because of the significant risk tor hypothytoidism even with subtotal thyroidectomy, total thvroidectomv has been advocated as another alternative in the surgical treatment of Graves' disease. Total or near-total thyroidectomy is associated with little or no increased risk for injury to the recurrent laryngeal nerve or permanent hypoparathyriodism. We have used three guiding principles to determine the extent of thyroidectomy. First, permanent hypoparathyroidism is a serious complication and should be avoided by modifying the operation to protect the parathyroid glands. Second, recurrent hyperthyroidism represents operative failure and usually requires ₁₃₁I for treatment, which negates the primary reason for which thyroidectomy is usually chosen in children. Third, hypothyroidism should not be considered a complication; instead, it should be viewed as an expected and easily treatable sequela of definitive therapy for Graves' disease. Therefore, total thyroidectomy is a viable option when the parathyroid glands can be preserved. If near-total thyroidectomy is to be performed, each remnant should weigh approximately 1 g or less to prevent recurrence of hyperthyroidism.

Neonatal Graves' disease is seen infrequently in infants and occurs in infants born to mothers with active or quiescent Graves' disease. This disease is caused by transplacental passage of thyroid-stimulating immunoglobulins and responds well to treatment with antithyroid medication.

Thyroid Neoplasms

Solitary Thyroid Nodule

In children, a solitary thyroid nodule or adenoma is uncommon (0.22% to 1.3%) compared with adults in which 4% of persons between 30 to 60 years of age were found to have one or more palpable thyroid nodules. However, children are relatively commonly diagnosed with what are believed to be thyroid nodules. Many times, careful examination reveals that these "nodules" are symmetrical enlargements of one lobe of the thyroid, multiple nodules, or Hashimoto's disease with a prominent thyroid. These misdiagnosed nodules may not even be related to the thyroid but instead are enlarged lymph nodes or a thyroglossal duct cyst. A palpable thyroid nodule in a child is of great concern because of an estimated 25% to 55% incidence of cancer. Although a significant number of thyroid nodules are malignant, follicular adenomas and colloid cysts are commonly seen. More rarely, Hurthle cell lesions or even medullary thyroid cancer may present as a solitary thyroid nodule.

The history and physical examination remain the most important information in evaluating thyroid nodules. A history of radiation therapy to the head or neck or a family history of endocrine tumors that indicate multiple endocrine neoplasia type II is very important. Information regarding the growth rate of the mass, the presence of other symptoms, and presence of hoarseness or trouble swallowing should be elicited. A careful examination of the neck can often determine whether a nodule is likely to be thyroid cancer. Children, in more than 70% of cases, may present with lymph nodes in the neck primarily low in the neck. Malignant thyroid conditions should also be suspected if the nodule is hard or adheres to surrounding structures.

Determining serum T₄, T₃, and thyroid-stimulating hormone may be helpful in the diagnosis of mild hyperthyroidism or in recognizing hypothyroidism associated with Hashimoto's disease. However, these tests generally do not contribute substantially to the management of solitary thyroid nodules.

Thyroid scintigraphy is frequently used in the evaluation of thyroid nodules.

Thyroid scintigraphy has substantial limitations in children and is primarily useful to detect thyroid tissue in other locations or a hot nodule that requires presurgical antithyroid drug therapy. Ultrasonography is also of limited value for evaluation of solitary thyroid nodules. Its principal use is to determine whether a nodule is cystic, solid, or mixed. A solid nodule has the greatest chance of being malignant, although most are benign. In addition, the presence of a cystic lesion does not exclude malignancy.

Thyroid hormone treatment has been used to distinguish benign from malignant nodules. Successful therapy is usually defined as a reduction in the size of the nodule of more than 50% over a few months. Several problems are associated with thyroid-suppressive therapy in children. First, the incidence of cancer in a palpable thyroid nodule in children is high. Second, evaluation of this therapy in adults concluded that such therapy had no significant effect on nodule size during a 6-month trial. Finally thyroid cancer may also respond to suppressive therapy, which would delay diagnosis and treatment. For these reasons, thyroid hormone therapy cannot be recommended in children without a prior diagnosis.

Needle biopsy has gained wide acceptance in the evaluation of thyroid nodules in adults. During the past decade, fine needle aspiration (FNA) placing a small needle in the module and applying negative pressure which draws cells into the needle, and looking at the cells under a microscope has been used on many patients with a high degree of accuracy. Papillary, medullary, and anaplastic carcinoma all have a typical appearance. Patients with nodules diagnosed as malignant or suspicious should proceed to surgery. Patients with benign aspirates can be followed closely with thyroid hormone therapy as long as they have no history of head and neck radiation. Another advantage of FNA is that fluid-filled cystic thyroid nodules. If the nodule is not felt after the fluid is removed and the nodule does not return, surgery is avoided. If a nodule is felt after aspiration, repeated FNA is done on the fluid which can be felt.

Fine-needle aspiration has not been used as extensively in children as in adults. One problem is the need for sedation or anesthesia in small children. Because of the higher rate of cancer in thyroid nodules, in children, these patients are spared an operation through use of FNA. Despite these potential drawbacks, this technique can contribute substantially to the evaluation of the pediatric patient with a thyroid nodule.

Thyroid Carcinoma

Approximately 13,900 total new cases of thyroid cancer will be reported in the United States in a year, but only 2.7% or 375 cases will occur in children. Most pediatric cancers occur in the 15- to 19-year-old age group and primarily are papillary carcinomas.

Risk Factors

Radiation therapy in the past was used widely for the treatment of benign conditions of the head and neck in children, such as acne, tonsillar enlargement of the thymus, and tinea capitis. These uses gradually stopped after the relationship of external radiation to thyroid cancer was made in 1950.²⁰ Radiation is more carcinogenic in children than in adults. Tumors may occur within the first 5 years after radiation exposure but probably peaks between 10 and 20 years later. Children who receive radiation therapy for treatment of Hodgkin's disease or other malignant conditions of the head and neck, or for bone marrow transplantation are at increased risk for thyroid cancer.

Pathology

Papillary carcinomas tend to be in multiple areas of the thyroid. They have little tendency to invade blood vessels. These tumors often spread to the regional lymph nodes, and they grow slowly. Follicular lesions more frequently invade blood vessels and spread to bone and lung. Many papillary tumors contain follicular portions. These mixed tumors, which are called follicular variants of papillary carcinoma, behave in a manner similar to that of other papillary cancers. Anaplastic carcinoma is rare in children but is associated with early death because of extensive local and widespread disease.

Clinical Presentation

Thyroid cancer is two to three times more common in girls than boys. It usually presents as one or more firm nodules in the neck. When examined microscopically, approximately 90% of these nodules will be found to be lymph nodes containing metastatic cancer. Children tend to present with larger nodules but may also have additional nodules.

The diagnostic workup of a suspected thyroid cancer is identical to that of a solitary thyroid nodule. A definitive diagnosis of cancer can only be made by biopsy. A chest x-ray should be obtained in all confirmed cases of thyroid cancer, but a substantial number of cases with spread to the lungs is not revealed until ¹³¹I scanning is done after surgery. ¹³¹I scanning is only effective if a complete thyroidectomy has been done.

Treatment

The therapy of thyroid cancer is primarily surgical supplemented by ¹³¹I, radiation therapy, thyroid hormone replacement ment, and occasionally external radiation. The appropriate extent of thyroidectomy for differentiated thyroid cancer continues to generate substantial controversy, especially with respect to children and adolescents. Those that support partial thyroidectomy and cervical lymph node dissection argue that total thyroidectomy does not reduce the overall mortality rate but does increase permanent hypoparathyroidism and injury to the recurrent laryngeal nerve. Others support total thyroidectomy plus cervical lymph node dissection. We advocate this approach for several reasons. First, total thyroidectomy can be done safely and permanent hypoparathyroidism and injury to the recurrent laryngeal nerve are rare. We have noted no cases of permanent low calcium from thyroid gland injury or injured recurrent laryngeal nerve in any child during the past few decades. Second, the incidence of spread to the lungs in children is high and total thyroidectomy allows early detection of such spread with a ¹³¹I scan. Third, total thyroidectomy decreases the rate of recurrence. Finally, following total thyroidectomy measurement of thyroglobulin levels allows one to detect persistent or recurrent cancer.

¹³¹I is important in the treatment of childhood thyroid cancer. Patients are scanned 6 weeks after total thyroidectomy. Those with uptake of radioactivity in the lungs, neck, or around the recurrent laryngeal nerve are treated with a therapeutic dose of ¹³¹I. The use of ¹³¹I depends on the amount of tumor in the neck.

Despite spread in the lymph nodes and even the lungs, the outlook for patients with papillary carcinoma is excellent. Many of the larger series in the literature have not reported a death in the past 20 years. Patients with a less favorable prognosis are young patients (< 10 yrs) who present with extensive lung spread with tracheal and laryngeal invasion. Although such cases are rare, these patients die of pulmonary insufficiency before any therapy can be effective.

Several prognostic factors have been investigated to predict which tumors will be aggressive. Tumors with nondiploid (abnormal number of copies) deoxyribonucleic acid (DNA) have been shown to cause a worse prognosis. Overexpression of the p21 ras protein or mutations of the N-ras gene have been shown to be independent prognostic indicators.

Medullary Carcinoma

Medullary Carcinoma of the thyroid occurs in children as a part of the multiple endocrine neoplasia (MEN) syndrome and less commonly as an individual cancer in older adolescents. Medullary thyroid carcinoma (MTC) accounts for only approximately 4% to 7% of all malignant tumors of the thyroid in adults.¹⁰ In children, this number is even lower; however, this tumor has received a tremendous amount of attention in recent years. The cancer is a hereditary in 20% to 30% of cases and it has high calcitonin which aids in diagnosis and follow-up of patients with MTC. However, the greatest interest has been generated by its involvement with MEN 2A, a cancer syndrome comprising MTC, adrenal gland pheochromocytomas, and hyperparathyroidism. Essentially all patients with die MEN 2A syndrome develop MTC. The syndrome is not usually clinically apparent before age 12 but is almost always clinically apparent before age 30. ' In contrast, patients with sporadic disease are almost always 30 years or older when the disease occurs, and these patients more commonly present with a single nodule of the thyroid. MTC in the MEN 2A syndrome is always bilateral, in multiple areas of the thyroid, and arises from C-cell hyperplasia. MTC has been found to be a more aggressive tumor than either papillary of follicular carcinoma, particularly in younger patients. MTC spreads at an early age to lymph nodes and eventually involves several distant sites, including the liver, lung, and bones.

Researchers in 1993 identified abnormalities in the ret protooncogene on chromosome 10; these mutations could identify, by means of a simple blood test, those patients who would develop the MEN 2A syndrome. We, along with several other centers, are now using genetic testing to identify children for prophylactic thyroidectomy.

Mutations of the ret protooncogene have also been identified in patients with the MEN 2B syndrome. The MEN 2B syndrome is similar to MEN 2A but is characterized by earlier age of tumor onset, usually by 5 years of age, and by developmental abnormalities that include ganglioneuromas throughout the alimentary tract.

Surgery

The thyroid is generally approached during surgery through a transverse skin line incision 1 to 2 cm above the clavicles. The length of the incision is determined by the size of the thyroid that must be removed. The neck muscles are separated in the midline and pulled to each side. The upper thyroid blood vessels are identified. The vessels are individually divided as they enter the thyroid. Once the upper portion is freed, division of the middle and lower thyroid veins allows the thyroid lobe to be mostly freed and pulled (rotated) toward the middle of the neck. Such rotation allows exposure of the branches of the main (inferior) thyroid artery and recurrent laryngeal nerve, both of which are preserved by careful dissection along the thyroid. The thyroid lobe (half of the thyroid) is removed as the "isthmus" between the two halves of the thyroid is divided. Lymph node dissection may be performed if thyroid cancer is present.

Complications

The structures of greatest importance in performing thyroidectomy are those of the recurrent laryngeal nerve, superior laryngeal nerve, and the parathyroid glands. Injury to the recurrent laryngeal nerve results in paralysis of the vocal cords. This may result in a normal but weakened voice, shortness of breath, or even a severely impaired voice and cough. Bilateral cord paralysis can result in either complete loss of voice or an airway blockage that requires a tracheostomy.

The external superior laryngeal nerve is usually not seen during thyroidectomy, although in 20% of cases, the nerve is at risk unless the upper thyroid vessels are divided carefully.

The parathyroid glands are frequently at risk during thyroid removal. Identification of the parathyroids while maintaining the blood vessels to them usually prevents damage to the parathyroids.

Information on the Parathyroid

This information is provided by the University of Michigan Department of Surgery, Section of Pediatric Surgery and is not intended to replace the medical advice of your doctor or health care provider. Please consult your health care provider for advice about a specific medical condition. For additional health information, please contact your health care provider or our offices.