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Chapter 563 Carcinoma of the Thyroid
Stephen LaFranchi
Epidemiology
Carcinoma of the thyroid is rare in childhood; the annual incidence in children <15 yr of age is approximately 2/100,000 cases, compared with an annual incidence at all ages around the world of 4-10/100,000 cases. Despite being widespread at discovery, thyroid cancer in children usually has an indolent course, resulting in a better survival rate than in adults.
Genetic factors and radiation exposure are important factors in the pathogenesis of thyroid cancer. Rearrangements of the RET proto-oncogene are found in 3-33% of papillary carcinomas and 60-80% of those occurring after irradiation, as in children in Belarus exposed to radiation after the nuclear accident at Chernobyl or in those who were exposed to external therapeutic irradiation in childhood. Inactivating point mutations of the p53 tumor-suppressor gene are rare in patients with differentiated thyroid carcinoma but are common in those with anaplastic thyroid cancer. Overall, 5-10% of cases of papillary thyroid carcinoma are familial and are usually inherited in an autosomal dominant manner.
The thyroid gland of children is unusually sensitive to exposure to external radiation. There probably is no threshold dose; 1 Gy results in a 7.7 relative risk of thyroid cancer. In the past, about 80% of children with cancer of the thyroid had received inappropriate therapeutic irradiation of the neck and adjacent areas during infancy for benign conditions such as “enlarged” thymus, hypertrophied tonsils and adenoids, hemangiomas, nevi, eczema, tinea capitis, and “cervical adenitis.” With the discontinuation of irradiation for benign conditions, this cause of thyroid cancer has vanished. The long-term survival of children who have received appropriate therapeutic irradiation of areas of the neck for neoplastic disease has made this cause of thyroid cancer and nodules increasingly prevalent; increased dose, younger age at time of treatment, and female sex are factors that increase the risk of thyroid cancer. Long-term risk data for cancer are sparse, but 15-50% of children who have received irradiation and chemotherapy for Hodgkin disease, leukemia, bone marrow transplant, brain tumors, and other malignancies of the head and neck have elevated levels of thyroid-stimulating hormone (TSH) within the 1st yr of therapy, and 5-20% progress to hypothyroidism during the next 5-7 yr. Most large groups of treated children have a 10-30% incidence of benign thyroid nodules and an increased incidence of thyroid cancer. The latter begins to appear within 3-5 yr after radiation treatment and reaches a peak in 15-25 yr. It is unknown whether there is a period after which no more tumors develop. Administration of iodine-131 for diagnostic or therapeutic purposes does not increase the risk of thyroid cancer.
Differentiated thyroid carcinoma has been reported in patients with chronic lymphocytic thyroiditis; it is not clear whether there is an increased risk of thyroid cancer in children with autoimmune thyroid disease. Conversely, lymphocytic infiltration within the thyroid cancer carries a more favorable prognosis, perhaps as a sign of an immune response to the cancer. One retrospective study indicated that the prevalence of thyroid cancer among children with autoimmune thyroiditis may be as high as 3%. The clinical course of autoimmune thyroiditis patients with cancer was distinguished by lymphadenopathy, a lack of response to levothyroxine therapy, and a hypoechogenic thyroid nodule.
Thyroid cancer has been reported in children with thyroglossal duct cysts, and it also has been found in children with congenital goiter. In these patients, and also in children with autoimmune thyroiditis and hypothyroidism, chronic TSH stimulation appears to play a pathogenic role.
Histologically, the carcinomas are papillary or follicular variant of papillary carcinoma (88%), follicular (10%), medullary (2%), or mixed differentiated tumors. All of the thyroid cancers in a retrospective study of children with autoimmune thyroiditis were papillary carcinomas. Thyroid cancer in children is more likely to be multifocal, with spread to regional lymph nodes at presentation. The type of tumor and the natural course of disease in irradiated and nonirradiated patients are the same except that multicentricity is more common in irradiation-induced cancer. Undifferentiated (anaplastic) thyroid neoplasms are rare in children and usually have a rapidly fatal course. Lymphomas and teratomas of the thyroid are also reported in children.
Girls are affected twice as often as boys. The average age at diagnosis is 9 yr, but the onset may be as early as the 1st yr of life. A painless nodule in the thyroid or in the neck is the usual initial evidence of disease. Rapid growth and large nodule size, firmness, fixation to adjacent tissues, hoarseness, dysphagia, and neck adenopathy are risk factors for thyroid cancer. Cervical lymph node involvement is often present at the time of initial diagnosis. Any unexplained cervical lymph node enlargement requires examination of the thyroid, which occasionally has a primary tumor too small to be felt; the diagnosis is based on biopsy results of the lymph node. The lungs are the most common site of metastases beyond the neck. There may be no clinical manifestations referable to them; radiologically, they appear as diffuse miliary or nodular infiltrations, principally in the basal portions. They may be mistaken for tuberculosis, histoplasmosis, or sarcoidosis. Other sites of metastasis include the mediastinum, axilla, long bones, skull, and brain. Almost all children are euthyroid, but rarely, the carcinoma is functional and produces symptoms of hyperthyroidism.
The most useful diagnostic test in the case of a solitary nodule is fine-needle aspiration (FNA). An ultrasonographic examination of the thyroid can provide information on the consistency of the nodule (solid vs cystic) and whether other nonpalpable nodules are present. A thyroid scan, preferably using 123I or 99mTc-pertechnetate, can provide information on trapping function and whether the nodule is “cold,” “warm,” or “hot.” The majority of cold nodules are benign. Neither ultrasound nor a thyroid scan can differentiate between a benign or malignant lesion. FNA specimens may be interpreted as benign, cancer, indeterminate (sometimes termed follicular neoplasm), or inadequate specimen. FNA experience in children shows a 5-10% false-negative rate and a 1-2% false-positive rate, with an overall diagnostic accuracy of 90-95%. Tests of thyroid function are normal, but Hashimoto’s thyroiditis has been associated with thyroid cancer.
Small (<1 cm) papillary carcinoma, the least-aggressive type, may be effectively treated by subtotal thyroidectomy and suppressive doses of thyroid hormone. However, because papillary carcinomas tend to be multicentric in children, and more than half have regional lymph node involvement at presentation, most patients should be managed by total thyroidectomy. For larger papillary carcinomas (>1.0 cm), and children with known follicular carcinoma, or with regional lymph node involvement, total thyroidectomy with excision of regional lymph nodes is the treatment of choice. There is no role for radical neck dissection. Thyroidectomy is usually followed by a dose (30-100 mCi) of 131I to ablate residual thyroid tissue or persistent disease, discovered by post-treatment whole body scan. Only patients who have undergone total thyroidectomy can be monitored by whole body radioiodine scanning and serum thyroglobulin. Newer guidelines suggest that children with isolated (or “incidental”) microcarcinomas (<1.0 cm) are cured by total thyroidectomy and therefore might not need radioactive iodine treatment.
After surgery, all patients should be treated with sodium L-thyroxine in doses sufficient to suppress TSH to the lower range of normal. Serum thyroglobulin (Tg) is an excellent marker for tumor recurrence, and periodic determinations of Tg levels should be performed. In patients who have undergone thyroid ablation, serum Tg level should be <1 ng/mL when thyroxine (T4) suppressive therapy is being received. Elevation of serum Tg during periods of thyroid hormone withdrawal or with recombinant TSH stimulation might discover patients with elevated Tg levels. Patients with an elevated serum Tg should undergo whole-body radioactive iodine uptake and scan and ultrasound examination of the neck to locate the source of Tg and plan appropriate management.
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