Chapter 563 Carcinoma of the Thyroid
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.
Although thyroid carcinoma is more widespread at discovery, the survival rate in children with thyroid carcinoma is better than in adults. The presence of regional lymph node spread does not affect survival in children. Even patients with recurrence of cancer or pulmonary metastases have survived many years. More than 95% of patients are alive 25 yr after initial treatment if the tumor was intrathyroid, <2 cm in diameter, and classified as grade 1. Greater tumor size, distant spread, and greater atypia are associated with increased cumulative mortality. Thyroid carcinomas that express telomerase and the IGF-1 receptor are more likely to show aggressive clinical features, and those that express the sodium-iodide symporter are associated with a lower risk of recurrence.
Alzahrani AS, Baitei EY, Zou M, et al. Clinical case seminar: metastatic follicular thyroid carcinoma arising from congenital goiter as a result of a novel splice donor site mutation in the thyroglobulin gene. J Clin Endocrinol Metab. 2006;91:740-746.
Amrikachi M, Ponder TB, Wheeler TM, et al. Thyroid fine-needle aspiration biopsy in children and adolescents: experience with 218 aspirates. Diagn Cytopathol. 2005;32:189-192.
Brignardello E, Corrias A, Isolato G, et al. Ultrasound screening for thyroid carcinoma in childhood cancer survivors: a case series. J Clin Endocrinol Metab. 2008;93:4840-4843.
Cooper DS, Doherty GM, Haugen BR, et al. Management guidelines for patients with thyroid nodules and differentiated thyroid cancer. Thyroid. 2006;16:109-142.
Corrias A, Cassio A, Weber G, et alStudy Group for Thyroid Diseases of Italian Society for Pediatric Endocrinology and Diabetology (SIEDP/ISPED). Thyroid nodules and cancer in children and adolescents affected by autoimmune thyroiditis. Arch Pediatr Adolesc Med. 2008;162:526-531.
Corrias A, Mussa A, Baronio F, et al. Diagnostic features of thyroid nodules in pediatrics. Arch Pediatr Adolesc Med. 2010;164(8):714-719.
Davies SM. Subsequent malignant neoplasms in survivors of childhood cancer: Childhood Cancer Survivor Study (CCSS) studies. Pediatr Blood Cancer. 2007;48:727-730.
Frio TR, Bahubeshi A, Kanellopoulou C, et al. DICER1 mutations in familial multinodular goiter with and without ovarian Sertoli-Leydig cell tumors. JAMA. 2011;305(l):68-77.
Handkiewicz-Junak D, Wloch J, Roskosz J, et al. Total thyroidectomy and adjuvant radioiodine treatment independently decrease locoregional recurrence risk in childhood and adolescent differentiated thyroid cancer. J Nucl Med. 2007;48:879-888.
Lando A, Holm K, Nysom K, et al. Serum thyroglobulin as a marker of thyroid neoplasms after childhood cancer. Acta Paediatr. 2003;92:1284-1290.
Lazar L, Lebenthal Y, Steinmetz A, et al. Differentiated thyroid cancer in pediatric patients: comparison of presentation and course between prepubertal children and adolescents. J Pediatr. 2009;154:708-714.
Machens A, Lorenz K, Thanh PN, et al. Papillary thyroid cancer in children and adolescents does not differ in growth patterns and metastatic behavior. J Pediatr. 2010;157:648-652.
Mehanna HM, Jain A, Morton RP, et al. Investigating the thyroid nodule. BMJ. 2009;338:705-709.
Mendelsohn AH, Elashoff DA, Abemayor E, et al. Surgery for papillary thyroid carcinoma. Arch Otolaryngol Head Neck Surg. 2010;136(11):1055-1061.
Palmer BA, Zarroug AE, Poley RN, et al. Papillary thyroid carcinoma in children: risk factors and complications of disease recurrence. J Pediatr Surg. 2005;40:1284-1288.
Peretz A, Leibermann E, Kapelushnik J, et al. Thyroglossal duct carcinoma in children: case presentation and review of the literature. Thyroid. 2004;14:777-785.
Rachmiel M, Charron M, Gupta A, et al. Evidence-based review of treatment and follow up of pediatric patients with differentiated thyroid carcinoma. J Pediatr Endocrinol Metab. 2006;19:1377-1393.
Ross DS. Radioiodine therapy for hyperthyroidism. N Engl J Med. 2011;364(6):542-550.
Savio R, Gosnell J, Palazzo FF, et al. The role of a more extensive surgical approach in the initial multimodality management of papillary thyroid cancer in children. J Pediatr Surg. 2005;40:1696-1700.
Seaberg RM, Eski S, Freeman JL. Influence of previous radiation exposure on pathologic features and clinical outcome in patients with thyroid cancer. Arch Otolaryngol Head Neck Surg. 2009;135:355-359.
Sosa JA, Tuggle CT, Wang TS, et al. Clinical and economic outcomes of thyroid and parathyroid surgery in children. J Clin Endocrinol Metab. 2008;93:3058-3065.
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563.1 Solitary Thyroid Nodule
Solitary nodules of the thyroid are common in children. They are found by palpation in approximately 2% of children aged 11-18 yr; ultrasound examination would likely show a higher prevalence, as it does in adults. Genetic factors play an etiologic role. Most thyroid nodules in children are benign, although several studies suggest that the proportion that are carcinomas is higher than in adults, varying from 2% to 40%. Considering the fact that thyroid nodules are common and thyroid cancer is rare, the true percentage of nodules that harbor cancer is probably closer to 2%. Children exposed to radiation have a high incidence of benign adenoma and carcinoma of the thyroid.
Benign disorders that can occur as solitary thyroid nodules include benign adenomas (follicular, embryonal, Hürthle cell), colloid (adenomatous) nodule, a simple cyst, lymphocytic thyroiditis, a thyroid abscess, and developmental anomalies such as thyroglossal duct cyst or hemiagenesis (Table 563-1). A suddenly appearing or rapidly enlarging thyroid mass can indicate hemorrhage into a cyst or benign adenoma. Ultrasonography is particularly useful in detecting cystic lesions. In most cases, the child is euthyroid, and thyroid function studies are normal. When lymphocytic thyroiditis is the cause of the nodule, thyroid antibodies are usually present. Ultrasonography shows diffuse hypoechogenicity. Radionuclide imaging reveals a moth-eaten appearance. Rarely, lymphocytic thyroiditis is associated with carcinoma of the thyroid.
The diagnostic studies to delineate the underlying cause include serum thyroid function tests, antithyroid antibody determinations, ultrasonographic examination of the thyroid, and fine needle aspiration (FNA). Radioiodine uptake and scan are useful when a suppressed serum TSH suggests an autonomous “hot” nodule. Response to a trial of suppressive T4 treatment to look for shrinkage of nodule size is not reliable. Although thyroid carcinomas generally occur as a solid, “cold” nodule, most “cold” nodules are benign lesions. FNA is useful in avoiding surgery for benign nodules. Surgery without delay is indicated when the nodule is hard or has grown rapidly, when there is evidence of tracheal or vocal cord involvement, and when there is enlargement of adjacent lymph nodes. All persons with a history of head or neck irradiation should have careful examinations of the thyroid at least every 2 yr and indefinitely.
Rarely, thyroid nodules are functional, producing hyperthyroidism (Plummer disease). These patients are discovered when thyroid function tests reveal a suppressed TSH, with T3 more elevated than T4 or free T4 levels. The uptake of radionuclide is concentrated in the nodule (“hot” or “warm” nodule), with absent uptake in the rest of the gland. Such nodules are usually benign, but a few instances of carcinoma in such cases have been reported. Treatment consists of surgical removal of the nodule.
Corrias A, Cassio A, Weber G, et al. Thyroid nodules and cancer in children and adolescents affected by autoimmune thyroiditis. Arch Pediatr Adolesc Med. 2008;162:526-531.
Hansen PS, Brix TH, Bennedbaek FN, et al. The relative importance of genetic and environmental factors in the aetiology of thyroid nodularity: a study of healthy Danish twins. Clin Endocrinol. 2005;62:380-386.
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563.2 Medullary Thyroid Carcinoma
Medullary thyroid carcinoma (MTC) arises from the parafollicular cells (C cells) of the thyroid and accounts for about 2% of thyroid malignancies in children. The majority of MTC cases are sporadic, but approximately 25% are familial, autosomal dominant disorders. Hereditary MTC is divided into three distinct syndromes: multiple endocrine neoplasia 2A (MEN2A), multiple endocrine neoplasia 2B (MEN2B), and familial MTC (FMTC). MTC is a result of mutations in the RET proto-oncogene on chromosome 10q11.2. Familial cases are associated with germ line mutations; most sporadic cases are caused by somatic cell mutations, but studies show that a small percentage, around 6-8%, are associated with germ line mutations and so can be passed on. Once an index case is diagnosed in a family, it is important to pinpoint the specific RET mutation and then screen all children in the family for the mutation. Thyroidectomy before the MTC has spread outside the gland represents the best chance for a cure.
The most common presentation of sporadic MTC is an asymptomatic, palpable thyroid nodule. When the tumor occurs sporadically, it is usually unicentric, but in the familial form, it is usually multicentric, and it begins as hyperplasia of parafollicular cells. X-rays can reveal dense, conglomerate, homogeneous calcification in the thyroid. Diagnosis of medullary carcinoma should lead to a careful search for associated tumors, particularly pheochromocytoma. No clinically recognizable manifestations result from the elevated serum levels of calcitonin or from the calcitonin gene-related peptide. Nonetheless, these tests are helpful in screening and monitoring therapy.
MEN 2A is an autosomal dominant disorder characterized by MTC, pheochromocytoma, and parathyroid hyperplasia. At least 19 different specific missense mutations of exon 10 or 11 of the extracellular domain of the RET gene have been described for MEN 2A and for cases of familial medullary thyroid carcinoma. DNA analysis permits unambiguous identification of carriers of the RET proto-oncogene mutation. Penetrance of MTC is close to 100%, but there is much variability in the other manifestations of MEN 2A. C-cell hyperplasia or MTC usually appears earlier than pheochromocytoma. Pheochromocytomas are often bilateral and may be multiple. Adrenal medullary hyperplasia is known to precede pheochromocytoma, but the detectable latent period is short. Hypercalcemia is a late manifestation and indicates hyperparathyroidism. The parathyroid glands might reveal chief-cell hyperplasia or only hypercellularity.
MEN 2B is an autosomal dominant disorder characterized by MTC and pheochromocytomas, but not hyperparathyroidism. The distinguishing feature of MEN 2B, also called the mucosal neuroma syndrome, is the occurrence of multiple neuromas and a characteristic phenotype. A missense mutation of the RET proto-oncogene in exon 16, the tyrosine catalytic domain of RET, is found in 93% of families; all patients have had the same point mutation.
The neuromas most often occur on the tongue, buccal mucosa, lips, and conjunctivae. Peripheral neurofibromas and café-au-lait patches may be present, and intestinal ganglioneuromatosis is common. Diffuse proliferation of nerves and ganglion cells is found in mucosal, submucosal, myenteric, and subserosal plexus involving the small and large bowel as well as the esophagus. The patients may be tall, with arachnodactyly and a Marfan-like appearance. Scoliosis, pectus excavatum, pes cavus, and muscular hypotonia are common. The eyelids may be thickened and everted, the lips patulous and blubbery, the jaw prognathic. Feeding difficulties, poor sucking, diarrhea, constipation, and failure to thrive can begin in infancy or early childhood, many years before the appearance of neuromas or endocrine symptoms.
Total thyroidectomy is indicated for all children who are shown by genetic studies to carry the RET gene mutation. Recognition of familial forms of this tumor is critical to the early diagnosis in children at risk. MTC develops at an earlier age in patients with MEN2B and is more aggressive than in MEN2A. MTC has been seen in a 6 mo old child with MEN2B and in a 3-yr old child with MEN2A. In MEN2A, there is genotype-phenotype correlation between the specific mutation and the onset of C-cell hyperplasia or MTC. Codon 634 mutations occur at an early age, whereas mutations at codons 618, 620, and 804 tend to occur at a later age. In young children, mutation analysis might help individualize the age of total thyroidectomy. All these children should be screened for pheochromocytoma before surgery. Monitoring the levels of calcitonin is useful in following the course of the disease after operation and in detecting metastatic lesions. Periodic screening for the development of pheochromocytoma and hyperparathyroidism is indicated. Metastases to the regional lymph nodes and to the liver are common. Death can result, but long survival is common.
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