Thyroid Nodules and Cancers in Children

Endocrinol Metab Clin N Am 34 (2005) 725–744

Thyroid Nodules and Cancers in Children Isil Halac, MDa, Donald Zimmerman, MDa,b,* a

Division of Endocrinology, Children’s Memorial Hospital, Chicago, IL, USA b Feinberg School of Medicine, Northwestern University, Chicago, IL, USA

The incidence of thyroid nodules in children is estimated to be 1% to 1.5% based on clinical examination [1]. Postmortem studies and ultrasonographic evaluation of the thyroid gland report an incidence of thyroid nodules up to 50% in adults [1]. In younger adults, between the ages of 18 and 39, postmortem studies show an incidence of 13% [2]. These studies suggest that the true incidence in children may be higher than the incidence found in clinical studies. Risk factors for the development of thyroid nodules include female sex, pubertal age, a family history of thyroid disease, previous or coexisting thyroid disease, and a history of a medical condition that may be steroid- or endocrine-related [3]. The risk of developing malignant thyroid disease in thyroid nodules in children is fourfold greater than the risk is among adults. Differentiated thyroid carcinoma is the most common pediatric endocrine tumor, constituting 0.5% to 3% of all childhood malignancies [4]. The thyroid gland is one of the most frequent sites of secondary neoplasms in children who receive radiation therapy for other malignancies. Differentiated thyroid carcinoma has been studied extensively in adults; however, the pediatric literature on differentiated thyroid carcinoma is much less complete. There is a female predominance in thyroid cancer among adults, a predominance that is not observed in children younger than 11 years old and is less prominent in adolescents than in adults [5,6].

* Division of Endocrinology, Children’s Memorial Hospital, 2300 Children’s Plaza, Box 54, Chicago, IL 60614. E-mail address: [email protected] (D. Zimmerman). 0889-8529/05/$ - see front matter Ó 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.ecl.2005.04.007 endo.theclinics.com

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Predisposing factors Environment A strong association exists between radiation exposure and the development of thyroid cancers. During the first half of the 20th Century, when radiation treatment was used in the treatment of benign conditions such as thymic enlargement of infancy, tonsillar and adenoidal infections, and tinea capitis, Duffy and Fitzgerald [7] reported that 36% of the pediatric patients diagnosed with thyroid cancer were exposed to radiation treatment earlier in life. After discontinuing radiation for these indications, the incidence of thyroid cancer in children decreased, but the incidence of thyroid nodules was unchanged. In 2000, Sklar et al [8] reported that patients with Hodgkin’s disease who were treated with radiation had a higher risk of developing not only thyroid cancers and nodules but also hypo- and hyperthyroidism. In the same study, Hodgkin’s disease survivors had thyroid nodules 27 times more frequently than did their siblings. Additionally, 20 among 1791 patients studied developed thyroid cancer; and the relative risk of developing thyroid cancer was 18.3 compared with the general population. Ninety-five percent of the Hodgkin’s disease patients in this study who developed thyroid cancer received radiation doses greater than 1000 cGy [8]. Other studies have reported the development of thyroid cancer after patients received lower doses of radiation. A number of reports [9,10] also suggest that patients undergoing bone marrow transplant preceded by radiation therapy are at an increased risk of developing thyroid cancer Therefore, these children should be followed closely for the development of thyroid cancer by examination for palpable thyroid nodules and by thyroid ultrasonography. If nodularity is found, it should be evaluated by performing a fine needle aspiration (FNA) biopsy of nodules larger than a few millimeters in diameter. The Chernobyl, Ukraine, accident in 1986 exposed large populations to radioactive iodine. An increase in thyroid cancer among exposed children was detected as early as 4 years after the accident [11]. Short-latency period tumors resulted from oncogenes such as RET/PTC3 that cause a high growth rate, structural de-differentiation, and greater aggressiveness. In comparison, long-latency period tumors resulted from oncogenes such as RET/PTC1, which cause a lower growth rate, greater differentiation, and less aggressiveness [12]. Pacini et al [13] compared the post-Chernobyl thyroid carcinoma in Belarussian children and adolescents with the naturally occurring thyroid carcinoma in French and Italian children and adolescents. The thyroid cancers affecting the Belarussian children were less influenced by sex, occurred in younger children, had greater aggressiveness at presentation, were more frequently papillary, and were more frequently associated with thyroid autoimmunity.

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Thyroid carcinoma may occur in the context of autoimmune disease. Therefore, prominent nodularity in the thyroid gland of a patient with autoimmune thyroiditis needs to be evaluated for malignancy with fine needle aspiration cytology. A number of other environmental factors may predispose to thyroid tumors. Volcanic areas have high incidences of thyroid cancer. In iodine-replete areas, thyroid cancers are usually papillary, whereas tumors in iodine-deficient areas tend to be follicular. Genetics Medullary thyroid carcinoma (MTC), which comprises 5% of childhood thyroid carcinomas, is a component of two genetic syndromes, multiple endocrine neoplasia type 2 (MEN 2) and familial medullary thyroid carcinoma (FMTC). MEN type 2A (MEN 2A) includes multicentric and often bilateral MTC, unilateral, or bilateral pheochromocytoma and hyperparathyroidism caused by parathyroid hyperplasia or adenoma. Some patients have cutaneous lichen amyloidosis. MEN type 2B (MEN 2B) includes MTC, pheochromocytoma, mucosal neuromas of the alimentary tract and subconjunctival areas, and skeletal abnormalities including marfanoid habitus, pectus excavatum, and slipped capital femoral epiphysis. MTC in MEN 2B presents at younger ages than in MEN 2A and in FMTC; and frequently it is detectable in infancy. MEN 2B-associated MTC also is more aggressive than MTC associated with MEN 2A or with familial thyroid carcinoma. Nonmedullary thyroid carcinoma is less frequently inherited than MTC. Up to 5% of these cancers are inherited [14]. These inherited nonmedullary thyroid cancers may occur in a number of heritable syndromes. Carney’s complex is an autosomal dominant syndrome caused either by a mutation in the protein kinase A type Ia regulatory subunit gene (PPKAR1A) or by another gene defect not yet characterized. Multiple endocrine organs may be affected. Micronodular adrenocortical disease produces Cushing’s syndrome. Other endocrinopathies include growth hormone-secreting pituitary tumors, male precocious puberty caused by hormonally active testicular tumors, and thyroid abnormalities. Thyroid abnormalities include hyperthyroidism, thyroid nodules (in 67% of patients), and thyroid carcinoma (in 3.8% of patients) [15]. The nonendocrine manifestations are skin and mucosal lentigines, cafe´ au lait-colored spots, blue nevi, other pigmented lesions, and myxomas of the heart, skin, and breast. Familial adenomatous polyposis (FAP) is an autosomal dominant precancerous condition caused by a germ-line mutation of the APC gene. This gene is located on chromosome 5 (5q21–q22) and is a tumor suppressor gene. FAP is characterized by multiple adenomatous polyps of the colon and rectum, osteoma of the bones (in a subtype referred to as Gardner’s

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syndrome), epidermoid cysts of the skin, desmoid tumors of the abdominal wall, and congenital hypertrophy of the retinal pigmented epithelium. One to 2% of patients with FAP also have thyroid carcinoma, which occurs mainly in female patients younger than 30 years of age. More than 95% of the FAP-associated thyroid cancers are papillary, and some show a cribriform pattern [16]. Cowden disease is an autosomal dominant disease that presents with hamartomas and other benign tumors of the skin and with tumors of the thyroid, breast, colon, endometrium, and brain. The genetic cause is a germline mutation of the tyrosine phosphatase tumor suppressor gene on chromosome 10q23 [3]. Findings in the thyroid may present as early as in childhood. Eighty-five percent of Cowden disease patients with thyroid disease present with multinodular goiter [17]. Significant thyroid lesions are multicentric follicular adenomas and adenomatous nodules that show a wide range of nonspecific cytoarchitectural patterns. Lesions may comprise oxyphil or clear cells, hyalinizing trabecular adenoma, or adenolipoma. Most of the thyroid cancers are of the papillary or Hu¨rthle cell types. Occasionally, follicular carcinomas, in addition to multiple benign follicular cell proliferations, occur in this setting. Harach et al [18] have suggested that multiple adenomatous goiters or multiple follicular adenomas occurring in children and young adults should alert the pathologist and physician to the possibility of an inherited trait such as Cowden disease. The tumors are usually benign and well demarcated, but because of multicentricity and the increased risk of recurrence or of progression to carcinoma, a total thyroidectomy should be advocated. Patients with ataxia-telangiectasia also are at a higher risk of developing primary carcinomas, including those of the thyroid and parathyroid. Pathology Thyroid cancer types are classified as tumors derived from the thyroid follicle (papillary, follicular, and insular), those derived from calcitoninproducing cells (medullary), and undifferentiated carcinomas (Fig. 1). In addition, insular thyroid carcinoma is less well differentiated than are follicular and papillary carcinomas. Undifferentiated or anaplastic thyroid carcinomas are almost unheard of in children. Papillary thyroid carcinomas (PTC), follicular thyroid carcinomas (FTC), and insular thyroid carcinomas secrete thyroglobulin, which is detectable in the peripheral circulation. Up to 72% of the thyroid cancers in children are of the PTC type [6]. Psammoma bodies, which are found in 40% to 50% of these tumors, are focal calcifications [19]. Their presence in lymph nodes is a strong sign of metastasis, and the lymphatic route is the principle route of metastasis of PTC. PTC is not usually encapsulated. Microscopic examination reveals papillary structures consisting of a fibrovascular core lined by a single layer of epithelial cells. The nuclei of the

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Fig. 1. Although both papillary (bottom left) and follicular (bottom center) carcinomas are derived from the thyroid-hormone-producing cells of the thyroid follicle, medullary thyroid carcinoma (bottom right) is derived from the calcitonin-producing cells of the interstitial areas between thyroid follicles. (Courtesy of the Mayo Clinic Foundation; with permission.)

epithelial cells are irregular and large and are folded and indented, with apparent intranuclear inclusions, which comprise invaginations of cytoplasm (Fig. 2). Nuclei also have a clear, pale-staining ground-glass appearance, with nuclear heterochromatin concentrated near the nuclear membrane. This appearance, which also is called ‘‘orphan-Annie-eyed’’ nuclei are well seen in fixed tissue but not in frozen section. PTC has several subtypes. In the follicular variant type of PTC, the most common variant, the neoplastic cells have the same nuclear features as in the typical PTC. However, follicular structures are interspersed among papillary structures. The clinical behavior is similar to pure PTC. In the diffuse

Fig. 2. In papillary thyroid carcinoma, papillary (fingerlike) structures consist of a fibrovascular core lined by a single layer of epithelial cells. The nuclei of the epithelial cells appear to overlap.

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sclerosing type, the patients are relatively younger compared with the general PTC population, and the clinical course is more aggressive, with more frequent lymph node and pulmonary metastases. Grossly, the diffuse sclerosing type of PTC is characterized by diffuse involvement of one or both lobes of the thyroid. Under the microscope, dense fibrosis, papillary carcinoma with marked squamous metaplasia and abundant psammoma bodies, heavy lymphocytic infiltration, and extensive lymphatic permeation are seen. The tall cell and columnar cell variants are rare and more aggressive types of PTC. In the tall cell variant, papillae are well formed, and the height of cells is at least twice their width. In the columnar type, nuclear stratification is prominent. Papillary thyroid microcarcinoma is the term given to PTC that is 1 cm or less in diameter. Although the prevalence found at autopsy is as high as 36%, the clinical prevalence is 1 per 100,000 [20]. Follicular carcinoma Follicular carcinoma of the thyroid makes up 18% of thyroid cancer in childhood [6]. FTC is found in higher prevalence in geographical areas with iodine deficiency. This could be one of the reasons FTC has decreased recently in the United States. It is more common among African Americans than among Asians or Caucasians. It is usually unifocal and unilateral. Grossly, the tumor may contain foci of hemorrhage, fibrosis, or calcification. These tumors may be well circumscribed and hard to differentiate from adenomas. A diagnosis is made by observing invasion of the capsule or of structures beyond the capsule such as blood vessel walls. Histologically, FTC has a solid growth pattern and is composed of uniform cells forming small follicles containing colloid. FTC may look quite similar to normal thyroid (Fig. 3), and in other cases, follicular differentiation may be less apparent. Unlike PTC, FTC metastasizes by the vascular route to the lungs, liver, bone, and brain.

Fig. 3. Follicular carcinoma of the thyroid has a more uniform structure than papillary carcinoma does. It is difficult to differentiate follicular carcinoma from follicular adenoma unless vascular invasion is observed.

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Insular thyroid carcinoma Poorly differentiated carcinomas are rare in childhood. Most patients with these tumors are older than 50 years of age. The youngest patient described with insular carcinoma is a 10-year old female [21]. Clinically, insular thyroid carcinoma presents as a rapidly growing mass, which may produce symptoms of pressure such as dyspnea, hoarseness, and dysphagia. Approximately two thirds of insular thyroid carcinomas may present with papillary or follicular features. Under the microscope, insular thyroid carcinoma presents as small follicles within solid clusters of tumor cells and foci of necrosis. Because of the small number of cases, the prognosis is not as well delineated as those of the more common thyroid tumors but is poorer than that of differentiated carcinomas. The recurrence rate may be as high as 80% [21]. Most insular cancer types present with involvement beyond the thyroid gland; therefore, aggressive treatment is warranted. Thyroglobulin can be used as a marker for tumor recurrence. Medullary thyroid carcinoma FNA cytology shows a lack of cellular cohesiveness. The cells have multiple nuclei with spindle shapes and a lack of prominent nucleoli. Medullary tumors can be immunostained for calcitonin if adequate material is available. If less than 10% of a tumor stains for calcitonin and if necrosis is prominent, the 10-year survival is reduced significantly [22]. The tissue histology consists of a solid mass of rounded, polygonal, or spindle-shaped cells and may have papillary or follicular patterns. Between the cells, amyloid, calcifications, or psammoma bodies may be seen. Familial MTC is multicentric, bilateral, and associated with C-cell hyperplasia. In the sporadic form, these features are rare. Pathogenesis As with other cancers, the tumorigenesis of thyroid carcinomas can be explained mainly by two mechanisms: activation of proto-oncogenes (Fig. 4) and inactivation of tumor suppressor genes. The proto-oncogenes include the RET gene in PTC and MTC. Tumor suppressor genes include p53 in FTC and PTEN in FTC and others. The overexpression of angiogenesis stimulators such as vascular endothelial growth factor C in papillary carcinomas and the underexpresion of angiogenesis inhibitors such as thrombostatin-1 in follicular thyroid carcinomas are other factors implicated in tumor growth. RET proto-oncogene RET is a proto-oncogene located on chromosome 10q11 [2], which is not expressed normally in thyroid follicular cells and is found in tissues derived

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Fig. 4. Oncogene formation. The chimeric transforming sequence is a constitutively active form of the proto-oncogene protein. It is formed by fusion of the tyrosine kinase domain (eg, of the RET or TRK proto-oncogenes) and an activating gene. (Courtesy of the Mayo Clinic Foundation; with permission.)

from the neural crest. It is a transmembrane receptor tyrosine kinase. Tyrosine kinases are part of the cellular signaling pathways and regulate cell functions such as proliferation, differentiation, antiapoptotic signaling, and neurite outgrowth (Fig. 5). Point mutations or overexpression causes dysregulation and can lead to various forms of benign proliferative conditions and cancers. The extracellular portion of RET interacts with ligand-binding proteins such as glial cell line-derived neurotrophic factor (GDNF) family receptors (GFR)a-1, -2, and -3. These receptors bind to ligands such as GDNF, neurturin, artemin, and persephin (which are members of the transforming growth factor b family) and then activate RET (Fig. 6).

Fig. 5. RET signaling. Some of the transduction pathways of RET signaling are shown. (Courtesy of the Mayo Clinic Foundation; with permission.)

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Fig. 6. The RET oncogene is a transmembrane protein. The extracellular portion of RET interacts with the ligand-binding protein GDNF family receptors (GFR)a-1, -2, and -3. These bind to ligands such as glial cell line-derived neurotrophic factor, neurturin, artemin, and persephin (which are members of the transforming growth factor b family) and then activate RET. GCNF, germ cell nuclear factor; P, phosphorus. (Courtesy of the Mayo Clinic Foundation; with permission.)

RET mutations have been found in papillary carcinoma of the thyroid. In PTC, somatic rearrangements involving the portion of chromosome 10 containing the RET gene cause activation of the RET gene in cells normally characterized by the absence of the Ret protein. RET/PTC1–10 genes have been described previously. RET/PTC are formed by attachment of the tyrosine kinase domain of RET to the 5-prime sequence of the other genes, including gene H4 in RET/PTC1 and ELE1 in RET/PTC3. These fusions result in ligand-independent dimerization and constitutive activation of these proteins (Fig. 7). Studies [23] have shown that RET rearrangement in thyroid carcinoma is found in high frequency not only in the children who were exposed to Chernobyl radiation fallout but also in patients receiving radiation treatment for benign and malignant conditions. In childhood PTC caused by radiation exposure, the incidence of RET rearrangement is reported to be between 50% and 70%, whereas in sporadic adulthood thyroid carcinomas, the incidence is between 5% and 30% [24–27]. RET proto-oncogene mutations rather than chromosomal rearrangements involving RET are found in medullary thyroid carcinoma (in both MEN and in sporadic medullary thyroid cancers). An international study by Eng et al [28] has shown that in MEN 2A, mutations occur at cysteine

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Fig. 7. RET/PTC proto-oncogene fusions are formed by attachment of the tyrosine kinase domain of RET to the 5-prime sequence of the other activating genes such as gene H4 in RET/ PTC1, type 1a regulatory subunit of protein kinase A (R1-a) in RET/PTC2 and ELE1 in RET/ PTC3. This may result from an intrachromosomal inversion, as illustrated in this figure, or from an interchromosomal translocation. (Courtesy of the Mayo Clinic Foundation; with permission.)

(Cys) codons 609, 611, 618, 620, and 634. These mutations occur in a region of the Ret protein in which cysteines normally form intramolecular disulfide bonds but in which an odd number of cysteines promotes intermolecular disulfide bonds. This results in constitutive dimerization, which activates signaling. Over 97% of the patients with MEN 2A had RET mutations. Ninety-five percent of the patients with MEN 2B have a mutation at codon 918. In this syndrome, the mutations are in the intracellular tyrosine kinase domain, which activates RET without dimerization. The mutations consist mostly of methionine-to-threonine transversion. Of the patients with familial MTC, 80% had mutations at cysteine codons 609, 611, 618, 620, and 634 [28]. In 1988, Ponder et al [29] demonstrated that a person presenting with apparently sporadic MTC has a 25% risk of having a familial form of MTC. Chromosomal rearrangements involving the NTRK1 proto-oncogene (a component of the high-affinity receptor for nerve growth factor) have been found in papillary thyroid carcinomas. Although these proto-oncogenes are encountered in fewer tumors than are rearrangements involving RET, they are particularly frequent in tumors of younger patients (Fig. 8). RAS oncogene Ras proteins have been shown to regulate cell growth, differentiation, and apoptosis, as well as influence processes such as cell migration and neuronal activity. RAS regulates a number of signaling molecules by

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Fig. 8. NTRK oncogene formation. NTRK1 (tropomyosin-rearranged kinase 1) is located on chromosome 1q21–q22. The fusion of the 3-prime end of the NTRK1 to the translocated promoter region (TPR) of different genes forms both TRK-T1 and TRK-T2. The TPR portion in TRK-T2 is longer and contains the NTRK1 transmembrane domain in addition to the tyrosine kinase domain. In TRK-T3, a TPR from chromosome 3 fuses with and activates TRK. (Courtesy of the Mayo Clinic Foundation; with permission.)

translocating them to the plasma membrane for activation. Ras proteins are guanosine triphospate (GTP)-binding proteins. Mutations in the guanosine (G) codons G12 and G13 in the GTP binding domain and G59 and G61 in the GTPase domain convert RAS to the active GTP-bound state, which results in constitutively active forms of Ras protein. Data regarding the RAS oncogene and thyroid carcinoma are variable. RAS mutations have been demonstrated in cold thyroid nodules, toxic thyroid adenomas, PTC, FTC, and anaplastic carcinomas at rates ranging from 7% to 92% [30]. However, a recent study [31] has shown no RAS mutations in papillary thyroid carcinomas. These differences in the RAS expression could be caused by differences in methodology or by environmental factors such as iodine deficiency or radiation exposure. BRAF mutations The BRAF protein is a member of the RAF proteins. These proteins are serine-threonine kinases that transmit a mitogenic signal to the nucleus. Any mutation that causes constitutive activation of this pathway leads to uncontrolled cell division. Fukushima et al [32] demonstrated that 53% of papillary thyroid carcinomas demonstrate BRAF mutations, especially valine-to-glutamic acid transversion at codon 599. This mutation was found in low frequency in children with thyroid cancer in Japan (3.2%), in children

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younger than age 15 years from Ukraine (0%), and in adolescents older than 15 years from Ukraine (24.2%) [33]. PAX8/PPARg fusion oncogene PAX8 is an important regulator of thyroid differentiation, growth, and function. In combination with peroxisome proliferator-activated receptor g (PPARg), it is believed to play a critical role in thyroid tumorigenesis. However, it is likely an early event in follicular thyroid tumorigenesis, occurring in both follicular adenomas and carcinomas. Alternatively, the fusion oncogene PAX8/PPARg is sufficient to promote carcinogenesis, but some follicular thyroid adenomas suppress malignant transformation through another mechanism [34]. Hepatocyte growth factor-scatter factor and hepatocyte growth factor-scatter factor receptor c-met Hepatocyte growth factor-scatter factor and hepatocyte growth factorscatter factor receptor c-met are important stimuli for the growth of thyroid tissue. Children and young adults with papillary thyroid carcinoma have shown an overexpression of these two factors in association with high risk of metastasis and recurrence [35]. p53 Tumor suppresser gene Mutation of the p53 gene has been found not only in thyroid cancers but also in other human tumors. p53 protects against cancer development by arresting the cell cycle, thus allowing DNA repair, and by allowing apoptosis of the damaged cells. The frequency of mutation of the p53 gene has been estimated in PTC to be between 0% and 75% (Table 1 lists other genes involved in thyroid cancers) [30]. Clinical presentation Thyroid cancer presents as a painless or tender thyroid mass in 88% to 91% of patients and as painless palpable cervical lymphadenopathy in 14% to 29% of patients [36,37]. Physical findings that suggest malignancy are hardness of the thyroid nodule and fixation of the nodule to surrounding tissues. Physical findings of the syndromes described above also should be sought. Local tenderness may be caused by hemorrhage inside a solid tumor or by cyst formation. In the study of 15 children with thyroid cancer by Arici et al [36], 33% of the patients presented with a solitary nodule, and 53% of the patients presented with a multinodular goiter. The palpable thyroid mass ranged from 1 to 5 cm. The isthmus was rarely involved. Most larger studies have described a much smaller frequency of multinodular goiter in association with thyroid cancer.

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Table 1 Genes involved in the pathogenesis of thyroid tumors Tumor histology

Gene

Comment

Papillary

RET/PTC

Rearrangements in up to 70% of radiation-exposed children and 30% of the sporadic cases in adults Rearrangements in children range from 0% to 24.2% Rearrangements rare in radiation exposed children Unlikely in sporadic childhood thyroid cancers; higher incidence in the follicular variant Rearrangements in association with high risk of metastasis and recurrence Alterations in the D-loop of the mitochondrial DNA have been demonstrated Underexpression in patients with Cowden disease Loss of function through methylation Loss of heterozygosity has been expressed Over-expression either in cytoplasmic pattern or in cytoplasmic-membranous pattern Also expressed in follicular adenoma; may have a role in malignant transformation Expressed in follicular adenomas and carcinomas Underexpression in follicular adenomas and carcinomas Loss of heterozygosity more common with metastasis Overexpression either in cytoplasmic pattern or in cytoplasmic-membranous pattern Over 95% of patients with MEN show RET rearrangements Overexpression in cytoplasmic pattern in over 75% of patients

BRAF NTRK-1(TRKA) ras HGF-SF and c-met mDNA PTENa p16a p53a c-erbB-2 Follicular

ras PAX-8/PPARg PTEN p53a c-erbB-2

Medullary

RET c-erbB-2

a

Tumor suppressor genes.

When an unexplained cervical lymph node is detected, the thyroid gland must be examined carefully. The primary tumor in the thyroid may be too small for palpation, and the diagnosis may be based on the results of the lymph node biopsy. Most thyroid cancers do not affect the surrounding thyroid tissue, and affected patients are usually euthyroid. Rarely, thyroid cancer may present with hyperthyroidism. Thyroid antibodies are present in up to 25% of the patients with thyroid carcinoma [38]. The most common sites of metastasis for PTC beyond the neck are the lungs, and lung metastases are more frequent in children than in adults. PTC patients with lung metastases often have no pulmonary symptoms. Radiographic findings include diffuse miliary or (less frequently) larger nodular infiltrations, especially located basally. Radiographic findings might be similar to those in tuberculosis, histoplasmosis, or sarcoidosis of the

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lungs. Lung findings may not be obvious on radiography or CT scans, but they are detected on total body radioiodine scans (Table 2 shows other sites of metastasis). Diagnosis The differential diagnosis of a thyroid nodule includes congenital abnormalities such as thyroid hemiagenesis, abscess, lymphocytic thyroiditis, nodular goiter, cyst, adenoma, and malignancies. A detailed history and family history should be obtained, especially of thyroid disorders and radiation exposure. A family history also should include questions about other components of MEN 2. Patients should be examined for physical findings seen in the syndromes associated with a higher risk of thyroid malignancies. Levels of thyrotropin (TSH), free thyroxine (T4), triiodothyronine (T3), calcitonin, thyroglobulin, and thyroid antibody levels should be measured. Thyroid ultrasonography can demonstrate if a nodule is solid or cystic and can show if there are other small nonpalpable nodules. In children, solitary nodules may have an approximately 30% to 50% chance of being malignant [39]. Thyroid lesions that are purely cystic are only rarely malignant. This author recommends fine needle aspiration of the thyroid under ultrasonographic guidance as the diagnostic approach. FNA might give false-negative results in 2.3% to 3.6% of the cases [6]. If the result is inconclusive or positive, the next step should be surgery. Thyroid scans provide information on iodine trapping function. Up to 30% of ‘‘cold’’ nodules are malignant [40]. ‘‘Hot’’ nodules are rarely malignant. Because FNA may show only follicular neoplasm, at times

Table 2 Sites of metastasis Histology

Site of metastasis

Papillary

Mainly lymphatic route Regional lymph nodes Lungs Bones Brain Mainly hematogenous route Lungs Liver Bones Brain Cervical lymph nodes Mediastinum Lung Liver Bone

Follicular

Medullary

Involvement at diagnosis (%) 75 13 d d d d d d d d d d

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a scan may help in estimating the probability of malignancy in thyroid neoplasms with such findings on FNA. In patients with a family history or suspicion of MEN, the RET oncogene mutations should be evaluated. Previously, calcitonin levels after the administration of calcium or pentagastrin were used to determine the presence of C-cell hyperplasia and carcinoma. C-cell disease is already present if the calcitonin results are positive. These tests are still of used to document the extent of tumor both pre- and postoperatively. In those families with MEN who have no detectable RET mutations, the methods of gene analysis should be checked, and a repeat of the studies in another reputable laboratory should be considered.

Treatment Once FNA cytology or biopsy establishes the diagnosis of thyroid cancer, the best surgical procedure for follicular-cell-derived thyroid carcinomas is either total thyroidectomy or near-total thyroidectomy (total on the side of the lesion and subtotal contralaterally). These procedures have advantages over less aggressive surgeries. Total thyroidectomy can be performed safely in experienced hands and with low complication rates. Thyroidectomy complications include permanent or transient hypoparathyroidism, major bleeding, laryngeal nerve damage, facial paralysis, Horner’s syndrome, and airway compromise. The risk of complications is higher in younger children, especially in those younger than 4 years old. Finally, this approach increases the specificity of thyroglobulin measurements (in tumors derived from the thyroid follicle) and the sensitivity of radioiodine scanning. Hay et al [41] has demonstrated that, in patients with low-risk papillary thyroid carcinoma who have undergone unilateral lobectomy, the risk of locoregional recurrence is significantly higher than in patients having bilateral surgery. In a recent multicenter study of 303 patients with papillary carcinoma, Taylor et al [42] have shown that total or near-total thyroidectomy improves overall survival. In 82 patients with follicular carcinoma, the extent of surgery did not have any effect on recurrence or survival. However, the interpretation of thyroglobulin levels and radioiodine scans may be less problematic with more extensive procedures. Especially in papillary and insular thyroid carcinoma, the examination of the local lymph nodes during surgery is crucial. In children with papillary carcinoma, clinical lymph node enlargement is reported to be 29%, and the presence of histologically confirmed cervical node metastases is reported to range from 73% to 90% [37,43]. Therefore, during surgery, lymph nodes in the tracheoesophageal groove are palpated and a biopsy is obtained. If the biopsy is positive, a modified neck dissection is performed. If the supraclavicular lymph nodes are enlarged and suspicious, biopsies of these also are performed.

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After surgery the patients begin thyroid replacement treatment to suppress TSH levels. Such suppression minimizes TSH-stimulated tumor growth. There are data in adults to show that low-risk patients (National Thyroid Cancer Treatment Cooperative Registry stages 1 and 2) may not require aggressive TSH suppression and that levels between 0.1 and 0.4 mU/L may be adequate. This study [44] followed patients for a mean of 4.5 years, so the long-term impact of nonaggressive suppression of TSH is still unclear. High-risk patients should undergo suppression to a level of less than 0.1 mU/L, keeping in mind the long-term complications of mild hyperthyroidism, such as decreased bone mineral density. In patients with nonmedullary thyroid cancer, total body scanning with 1 to 5 mCi of iodine 131 (131I) or 1 to 5 mCi of 123I is recommended at 6 to 8 weeks after surgery to detect tumor in the thyroid bed or in other locations. Before total body scanning, the TSH level should be greater than 35 mU/L. During the 6- to 8-week period before scanning, replacement with T3 may be used. Because T3 has a shorter half-life (24 hours) compared with T4 (1 week), the period of hormone withdrawal and exposure to elevated levels of TSH is shorter with use of T3. T3 treatment should be discontinued 2 weeks before scanning. Another method of preparing patients for scanning is to administer intramuscular IM recombinant TSH. If uptake is evident in the thyroid bed, then FNA under ultrasonographic guidance can be used to distinguish between uptake in a benign thyroid gland remnant and uptake in a tumor focus. Uptake in the neck away from the thyroid bed is very likely to be a metastatic tumor. If the findings suggest a tumor that is not readily or safely treatable with surgery, therapeutic radioiodine may be given. Therefore, thyroid replacement treatment should be withdrawn before the procedure. Therapeutic radioiodine uptake by the thyroid and cervical lymph nodes may be affected adversely by the diagnostic administration of 131I, a phenomenon that has been termed ‘‘stunning.’’ The administration of 123I for diagnostic scanning avoids this stunning of tumor uptake of therapeutic radioiodine [45]. Some investigators continue to use 131I for scanning but, because 131I scans may be more sensitive than 123I scans, use doses low enough to minimize the possibility of stunning [46]. 131I is the isotope of choice for treatment. Dosing may follow empirical guidelines similar to those used in adults. However, studies that have modeled radiation exposure in children suggest the use of 131I doses that are reduced from adult doses in proportion to body weight or to body surface area [47]. The ‘‘routine’’ ablation of normal thyroid remnants should be reserved for high-risk tumors such as insular tumors and high-grade, large, or invasive papillary or follicular tumors. Complications of therapeutic radioiodine include infertility problems and secondary malignancy in organs that concentrate radioactive iodine, such as the salivary glands, bowel, and bladder. In patients with papillary, follicular, or insular tumors, serum thyroglobulin and thyroglobulin antibodies should be monitored after surgery.

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The reappearance of circulating thyroglobulin levels greater than w2.5 ng/ mL suggests after total thyroid ablation indicates the persistence or recurrence of a tumor. Antibodies are present in approximately 15% to 25% of thyroid cancer patients and may interfere with the measurement of thyroglobulin levels. No immunoassay is totally free of interference by thyroglobulin autoantibodies. The outcome of differentiated thyroid carcinoma is regarded as favorable. At 10 years, the mortality from the disease tends to be approximately 1% [6]. A long-term follow up of these patients showed an overall survival rate of 100% at 10 years, even in patients with distant metastasis, and with long-term follow-up to 52 years, 5% to 7% of patients died of thyroid cancer or related complications [48]. In MEN 2 and in familial medullary thyroid carcinoma, total thyroidectomy is the surgical choice. If the patient is a known RET carrier, thyroidectomy is prophylactic if performed before the calcium stimulation test is positive. In RET-positive MEN 2A children, thyroidectomy should be performed before age 5, and in RET-positive MEN 2B patients, thyroidectomy should be performed within the first few months of life. Calcitonin levels should be measured before surgery and can be used thereafter as a tumor marker. A total thyroidectomy should be accompanied by central neck dissection. If central nodes are positive, then the dissection of lateral compartments is needed. Postoperatively, patients are started on regular thyroid replacement therapy but not to suppress TSH levels because the C cells are not TSH-responsive. Calcium-stimulated calcitonin measurements should be performed postoperatively and at regular intervals thereafter for follow-up of medullary tumors. If basal calcitonin levels are elevated, then stimulation testing is unnecessary. Saad et al [49] have demonstrated that the adjusted survival rates of all the patients with MTC at 5 and 10 years were 78.2% and 61.4%, respectively. Patients with MEN 2A had much better survival rates than patients found to have sporadic MTC. The patients with stages 1 and 2 had better survival rates. In patients with MEN 2B presenting with MTC, 5- and 10-year overall survival rates were 85% and 75%, respectively [50].

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