Goiter refers to an abnormally enlarged thyroid gland. The etiology in children is broad and geographically different ( Fig. 72.1 ). In many parts of the world, endemic goiter is related to dietary iodine insufficiency. However, in developed countries, goiters can also be related to inflammatory conditions or nodular enlargement. The term simple goiter is used to refer to thyromegaly in a euthyroid person without a known cause such as iodine deficiency or an autoimmune condition. A study from Eastern Europe, where drinking water was iodinated, showed that simple adolescent goiters were the most common cause of thyromegaly, followed by autoimmune thyroiditis. Physiologically, a defect in hormone production, autoimmune diseases, or a response to an inflammatory condition can all result in diffuse thyroid enlargement. Goiters can be either diffusely enlarged or nodular and are functional (toxic) or nonfunctional (euthyroid). Children with thyroid enlargement are often euthyroid and asymptomatic. Resection is rarely indicated, unless there are symptoms of mass effect.

This 15-year-old patient was diagnosed with Graves disease as the cause of his thyromegaly. Medical therapy was not effective, and he elected total thyroidectomy because of swallowing difficulty.

The differential diagnosis for diffuse thyroid enlargement is seen in Box 72.1 , illustrating that a goiter is a typical but nonspecific finding of acquired thyroid disease with many etiologies. The patient’s history and exam will reveal them to be hyperthyroid, hypothyroid, or have no signs and symptoms, thereby guiding the differential diagnosis. Workup begins with plasma free T4 and TSH levels. A euthyroid patient (normal T4 and TSH levels) with thyromegaly has a simple colloid goiter. In addition, serum thyroid antibody levels are normal, and ultrasonography (US) will show uniform enlargement of the gland. The natural history of a simple goiter is not well known. One study of adolescents reported that nearly 60% of the glands were normal in size 20 years after diagnosis, but other studies have shown that a small percentage of patients with simple colloid goiter progressed to Hashimoto’s thyroiditis. ^, Treatment of the thyroid enlargement with thyroid hormone may not significantly improve resolution of the goiter. Resection may be indicated because of the size and mass effect but is uncommon.

Chronic lymphocytic (Hashimoto) thyroiditis, also known as chronic autoimmune thyroiditis, is the most common cause of acquired hypothyroidism in children, with a prevalence of 1%–2% and a 4:1 female predominance. It is another cause of diffuse thyroid enlargement, and goiter is the most common presentation of Hashimoto thyroiditis in children. Laboratory workup should include serum TSH and free T4 and antithyroid antibodies. About 85%–90% of children with Hashimoto thyroiditis will have high levels of antithyroid peroxidase (TPO) antibodies, and an almost equal number will have high antithyroglobulin antibodies. An additional 10% will have thyrotropin receptor blocking antibodies. In rare circumstances, autoantibodies cannot be detected.

Thyroid imaging is usually not indicated and may even be falsely negative. However, in one study, follow-up US in 50% of patients after an initial negative US in children with other signs of chronic lymphocytic thyroiditis showed the typical changes within 7 months. The principal US finding is diffuse thyroid hypoechogenicity, which is nonspecific. In as many as one-third of adolescent patients, the thyroiditis resolves spontaneously, the gland becomes normal, and the antibodies disappear. Therefore, expectant management should be considered.

Exogenous thyroid hormone should be administered in the hypothyroid patient. However, in euthyroid children, it is more controversial, with some studies showing that thyroid hormone is ineffective in reducing the size of the goiter, whereas more contemporary studies show a decrease in goiter or thyroid size in euthyroid children. ^, However, it can be difficult to determine how much of this decrease in size is related to the therapy or to the natural history of the disease.

Subacute (de Quervain) thyroiditis is a viral inflammation of the thyroid gland that is unusual in children. These patients present with a swollen, painful, and tender thyroid. Mild thyrotoxicosis from injury to the thyroid follicles can result in release of thyroid hormone, which in turn causes an increase in T3 and T4, with a decreased TSH. Decreased radioactive iodine uptake occurs due to thyroid follicular cell dysfunction. This finding distinguishes subacute thyroiditis from Graves disease. Granulomas and epithelioid cells can be found on histologic examination. Treatment is supportive, utilizing nonsteroidal antiinflammatory agents or corticosteroids. Occasionally, if the initial hyperthyroid phase is symptomatic with a low serum TSH, then treatment with beta-blockade may be needed. Additionally, if the subsequent hypothyroid phase is severe and prolonged, short-term therapy with thyroid hormone replacement may be needed. Subacute thyroiditis usually lasts 2–9 months, with complete recovery being the norm.

Acute suppurative thyroiditis is a bacterial infection of the gland characterized by fevers, chills, hoarseness, dysphagia, and an inflamed lobe. Patients are usually euthyroid, although rarely they can have transient hyperthyroidism. Management is intravenous antibiotics and abscess drainage, if necessary. Occasionally, a congenital pyriform sinus tract may predispose the patient to infection. This is a third branchial cleft remnant that can communicate with the left lobe of the thyroid and cause inflammation. If the congenital sinus tract is present, excision with left hemithyroidectomy is indicated. The thyroid gland typically recovers completely in acute suppurative thyroiditis.

Graves disease, or diffuse toxic goiter, is the most common cause of hyperthyroidism in childhood, accounting for approximately 15% of childhood thyroid disease. This disease was initially described by Sir Robert Graves in the early 19th century. The incidence of Graves disease is thought to be rising, and is more frequent in children with other autoimmune diseases. It is estimated that Graves disease affects 1 in 10,000 children in the United States. Although it can occur at any age, it increases in frequency with age. It peaks during adolescence, and girls are affected more frequently than boys. In Graves disease, the thyroid gland is infiltrated with lymphocytes, with loss of tolerance to multiple thyroid antigens and production of antibodies that activate the TSH receptor. ^, This results in undetectable TSH levels in the serum, and very high free T4 and free T3 levels, leading to clinical signs and symptoms of hyperthyroidism. TSH receptor antibodies are present in most patients, although with variable titers. Antibody levels are higher in children 5 years of age or younger, and in those with a severe initial clinical presentation. The presence of TSH receptor antibodies definitively establishes the diagnosis, but their absence, or low concentration, does not exclude the diagnosis and may be due to assay insensitivity or intrathyroidal production of autoantibodies. ^,

Graves disease usually develops slowly over several months. Initial symptoms include those typical of hyperthyroidism: nervousness, emotional changes, insomnia, and declining school performance followed by weight loss, sweating, palpitations, heat intolerance, and general malaise. A smooth, firm, nontender goiter is present in most cases. Scattered epidemiologic reports of disease clustering supports an infectious etiology for Graves disease. However, genetic susceptibility likely also plays a role.

Treatment is aimed at decreasing the production and secretion of thyroid hormone as successful methods for correcting the immunologic defect are not known. Current management includes antithyroid medications, ablation with radioactive ¹³¹ I, and thyroid resection. In the United States, most pediatric endocrinologists initiate therapy with methimazole (MTH), as propylthiouracil (PTU) has fallen out of favor due to an association with severe liver failure and a subsequent black box warning from the U.S. Food and Drug Administration (FDA). Both medications reduce thyroid hormone production by inhibiting follicle cell organification of iodide and the coupling of iodotyrosines. These medications possess some immunosuppressive activity as evident by a reduction in antithyroid antibodies. MTH has increased potency, a longer half-life, and improved compliance due to once daily dosing. The dosing is 0.5–1 mg/kg/day with a maximal dose of 30 mg/day. The daily dose of MTH should be reduced to 10 mg when the patient is euthyroid, with normal T3 and T4 levels. This results in a decrease in thyroid gland size in 50% of patients. Thyroid hormone levels should be monitored. Thyroid enlargement with therapy signals either an intensification of the disease or hypothyroidism due to overtreatment.

Side effects of MTH include nausea, minor skin reactions, urticaria, arthralgias, arthritis, headaches, bleeding, hepatic toxicity, and fevers. These are often dose related and generally occur during the first 3–6 months of therapy but can occur after a year of exposure. ^, The most serious reaction is agranulocytosis, which fortunately occurs in fewer than 1% of patients. With any signs of illness, total and differential cell counts should be obtained to assess for agranulocytosis. Treatment with parenteral antibiotics during the recovery period is recommended.

The goal of medical treatment of Graves disease is to allow natural resolution of the underlying autoimmune process. In general, the disease remission rate is approximately 25% after 2 years of treatment, with a further 25% remission every 2 years thereafter. A contemporary study showed that the cumulative remission rate increased with the duration of antithyroid drug treatment, up to 5 years. Remission was achieved in 46% of patients overall, but children have a lower likelihood of remission compared with adults. Additionally, prepubertal children are known to have an even lower rate of remission. ^,

The thyroid gland must be ablated or resected if resistance or severe reactions to the antithyroid medications develop. Additionally, if remission has not been achieved after 5 years of treatment, definitive therapy with either resection or ablation with radioactive ¹³¹ I should be considered. ^{, ,} Patients should also consider definitive therapy if they are unable or unwilling to comply with medication administration, if they have persistent symptoms despite normalization of thyroid hormone levels, or if they are at a transition time in life such as moving away for college. The goal of definitive therapy is permanent hypothyroidism, which is associated with a relative ease of management, low risk related to thyroid replacement therapy, a more predictable disease course, and less frequent laboratory surveillance. Considerations when selecting between surgical resection and radioactive ¹³¹ I for children and adolescents include age, compressive symptoms, size of the goiter and presence of nodules, accessibility to a high-volume pediatric thyroid surgeon, associated proptosis, pregnancy, and patient/family choice. Total thyroidectomy should be considered over ¹³¹ I therapy: for children under 10 years of age, goiters more than three times the size of a normal gland, with compressive or airway symptoms, presence of nodules, significant proptosis with active eye disease, desire for rapid achievement of hypothyroidism, and if pregnant or considering pregnancy ( Table 72.1 ). Both resection and ablation with radioactive ¹³¹ I have complications. The advantages of ¹³¹ I therapy include effectiveness, safety, ease of administration, and relatively low cost. The possibility of teratogenic or carcinogenic effects of ¹³¹ I in children and adolescents is also a concern. There is a failure rate with ablation and some patients will require surgery or further ablation in these rare cases.

For patients undergoing thyroidectomy for Graves disease (see Fig. 72.1 ), antithyroid medication should be administered to decrease T3 and T4 levels into the normal range before operation. Additionally, β-blocking agents, such as propranolol, may be used to ameliorate the adrenergic symptoms of hyperthyroidism. In addition, Lugol’s solution or SSKI (potassium iodide), 7–10 drops per day, can be administered for 4–7 days before thyroidectomy to reduce the vascularity of the gland. During the operation for Graves disease, it is important to assess for thyroid storm, which is an acute life-threatening hypermetabolic state due to increased thyroid hormone. This will present with fever, hypertension, and tachycardia and recognition and treatment is vital to prevent further decompensation.

Hypothyroidism can be secondary to impaired function of the thyroid gland (primary hypothyroidism), or due to impairment of the hypothalamic and/or pituitary control of thyroid function (central hypothyroidism). Surgical treatment is rarely needed. Approximately 90% of pediatric hypothyroidism is congenital, with an incidence of 1:2000 births. Congenital hypothyroidism is detected by neonatal screening programs and results from dysgenesis of the thyroid gland, or failure of an anatomically normally developed thyroid gland to produce thyroid hormone appropriately.

The most common acquired hypothyroidism in children is autoimmune thyroiditis, which results in primary hypothyroidism secondary to a T-cell–mediated response to thyroid autoantigens leading to fibrosis of the gland. Other causes of thyroiditis, iodine deficiency, as well as a host of medications, can lead to hypothyroidism in children as well.

Thyroid nodules are less common in children than adults but are more concerning because they have a higher incidence of malignancy (20%–36%). ^, Nodules are often detected by clinician palpation or by the patient’s family members. Much less frequently, they are incidentally found by radiographic imaging for other purposes. Interestingly, in one study, those nodules discovered by family members were larger and had higher rates of metastatic disease. Appropriate and prompt diagnosis, evaluation, and management are important to decrease disease progression. Various histopathology is found in children who undergo an operation for thyroid nodules ( Table 72.2 ). ^{, ,} Other diagnostic possibilities for thyroid nodules include cystic hygroma, thyroglossal duct remnant, branchial cleft cyst, and germ cell tumor.

US is considered the standard diagnostic modality for thyroid nodules ( Fig. 72.2 ). The Thyroid Imaging Reporting and Data System (TIRADS) has been created to uniformly classify US characteristics of thyroid nodules, and the American Thyroid Association (ATA) has utilized these characteristics to try to identify the malignancy risk from the US findings. ^, Specific US findings lead to a nodule’s characterization as being benign, very low suspicion, low suspicion, intermediate suspicion, or high suspicion of malignancy risk as described by the 2015 ATA Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer ( Fig. 72.3 ). In children, US characteristics and clinical context are more important than size. In adults, a nodule size of 1 cm is used to determine the need for fine-needle aspiration (FNA). ^, US features such as hypoechogenicity, irregular margins, and increased intranodular blood flow are more common in malignant lesions ( Table 72.3 ; see Fig. 72.2 ). Based on US findings and clinical context, children with thyroid nodules undergo a different workup and treatment algorithm than adults, based on the ATA management guidelines specific to patients below the age of 18. The first step in the workup is measurement of TSH. If it is suppressed, nuclear thyroid scintigraphy follows. A hyperfunctioning nodule should be resected with a thyroid lobectomy and isthmusectomy. Hypofunctioning nodules and those without TSH suppression should undergo FNA using US. In children, it is recommended that FNA should be performed with US guidance. ^{, ,} Benign nodules or those with inadequate or nondiagnostic FNA should undergo surveillance. Malignant lesions should be treated according to guidelines described in the following section. Indeterminate or suspicious nodules on FNA should undergo resection, most commonly thyroid lobectomy with isthmusectomy, with further management based on the histopathology (see Fig. 72.3 ). Multigene genomic classifiers are increasingly being used to help dictate care based on the genetic risk profile. ^, Molecular analysis can be helpful in differentiating benign and malignant thyroid nodules with indeterminate cytology. Patients with genetic abnormalities and indeterminate cytology should be considered for resection.

A teenager presented with a large right thyroid mass that was found to be papillary cancer. Ultrasound features that are suggestive of thyroid malignancy include hypoechogenicities, irregular margins, and increased intranodular blood flow.

The management algorithm for children with a suspicious thyroid nodule based on the 2015 ATA Management Guidelines for children is depicted. (1) the algorithm assumes a solid or partially cystic nodule ≥1 cm or a nodule with concerning ultrasonographic features in a patient without personal risk factors for thyroid malignancy. (2) A suppressed TSH indicates a value below the lower limits of normal. (3) Refers to parathyroid cancer or medullary thyroid cancer management guidelines. (4) Surgery can always be considered based on suspicious ultrasound findings, concerning clinical presentation, nodule size >4 cm, compressive symptoms, and/or patient/family preference. (5) Surgery implies lobectomy plus isthmusectomy in most cases. Surgery may be deferred in patients with an autonomous nodule and subclinical hyperthyroidism, but FNA should be considered if the nodule has suspicious features for papillary thyroid cancer. Intraoperative frozen section for indeterminate and suspicious lesions is helpful. Total thyroidectomy should be considered for nodules suspicious for malignancy on FNA. 6, One should consider completion thyroidectomy ± radioactive iodine versus observation ± TSH suppression based on final pathology. FNA, Fine-needle aspiration; US, ultrasound.

From Gary L. Francis et al. Management Guidelines for Children with Thyroid Nodules and Differentiated Thyroid Cancer. The American Thyroid Association Guidelines Task Force on Pediatric Thyroid Cancer. Thyroid, Volume: 25 Issue 7: July 10, 2015. Used with the permission of Mary Ann Liebert, Inc. publishers.

The incidence of thyroid carcinoma is increasing in both children and adults, but overall the mortality remains stable. ^, According to one large database study of childhood thyroid cancer, the histopathology of thyroid cancer in children is similar to that in adults: 80% papillary, 10% follicular, 5% medullary (MTC), and 2% other types. In the same study, thyroid cancer was found to be limited to the thyroid gland at the time of diagnosis in 42%, and in regional lymph nodes in 46%.

Children with thyroid carcinoma present with more advanced-stage disease, a higher incidence of lymph node and pulmonary metastases, but have a lower mortality rate than adults. ^, Prepubertal children have a greater degree of extrathyroidal extension, lymph node involvement, and lung metastases at diagnosis compared with adolescents. ^,

Exposure to radiation is a significant risk factor for developing thyroid cancer as well as nonmalignant thyroid disease. A 62-fold increase in thyroid tumors was noted in the Republics of Belarus and Ukraine after the 1986 Chernobyl nuclear power plant catastrophe. The tumors presented with increased tumor spread, local invasion, and nodal metastases. The use of radiation for diagnostic purposes has also been linked to an increase in childhood cancers. It is estimated that computed tomography (CT) scans increase the risk of malignancy as much as one fatal cancer per 1000 CT scans. ^,

Thyroid cancers constitute about 10% of second malignancies, with treatment for previous malignancies being a risk factor for thyroid cancer. Hodgkin lymphoma is the most common malignancy associated with a subsequent thyroid cancer, followed by non-Hodgkin lymphoma and leukemia. ^, Female gender, younger age at exposure, and time since exposure were found to be significant modifiers of the radiation-related risk of secondary thyroid cancer. This is related to both previous radiation exposure to the neck, or less commonly, chemotherapeutic treatment with alkylating agents.

The disparity in behavior of the different histologic subtypes of thyroid cancer may be related to various molecular findings. RAS proto-oncogene mutations are found in about 20% of papillary tumors and 80% of follicular tumors. RAS is frequently activated in benign follicular adenomas, suggesting this genetic event occurs early in the transformation process. About 35% of papillary thyroid cancers have an activating mutation of the RET proto-oncogene. The RET protein is a receptor tyrosine-kinase molecule, which functions on an intracellular level to regulate proliferation or differentiation. It may be responsible for the development of MTC. Specific point mutations are associated with the multiple endocrine neoplasm (MEN) type 2 (MEN 2A, MEN 2B) syndromes and familial MTC (FMTC). In addition, as many as 40% of patients with sporadic MTCs possess RET mutations. Integrating molecular testing is becoming front-line management for pediatric thyroid nodules, both malignant and those with indeterminate cytology on FNA. Some centers recommend that all pediatric patients with undetermined cytology undergo somatic oncogene testing to guide surgical care. ^{, ,}

There are several hereditary syndromes with specific known chromosomal abnormalities that increase the risk of both malignant and nonmalignant thyroid neoplasms. For example, familial adenomatous polyposis, with an abnormality of the APC gene (5q21–q22 chromosomal location), results in an increased risk of papillary thyroid cancer. Patients with familial non-MTC cancers have more aggressive tumors with increased rates of extrathyroid extension, lymph node metastases, an earlier age at disease onset, and increased severity in successive generations. The ATA recommends that patients at an increased risk of developing familial thyroid cancer should be referred to centers of excellence (COEs) to obtain appropriate evaluation, follow-up, genetic counseling, and treatment.

Thyroid carcinoma usually presents clinically as a thyroid mass, sometimes with enlarged cervical lymph nodes. Regional lymph node metastases are present in three-fourths of children at the time of diagnosis. ^{, ,} The diagnosis of thyroid carcinoma requires appropriate imaging and histologic examination, with the workup of a suspicious thyroid nodule including US and US-guided FNA as described previously. Suspicious or intermediate results on FNA mandate operative resection, usually lobectomy and isthmusectomy, with completion thyroidectomy or observation with or without TSH suppression depending on final histopathology. The Bethesda classification for cytology, with associated categories of cancer risk, is accurate in adults. In children, it accurately identifies benign nodules (Bethesda Category II). However, other categories (Bethesda Category III–V), which have lower rates of malignancy in adults, have very high rates of malignancy in children.

The preoperative workup for a child with a newly diagnosed papillary thyroid carcinoma on FNA includes a comprehensive neck US including central and lateral neck compartments with a high-resolution probe and an experienced ultrasonographer. The goal of US assessment is to identify locoregional metastases and therefore direct FNA of suspicious lymph nodes. Additional cross-sectional imaging for operative planning should be considered in patients with bulky disease or vocal cord paralysis. Performing a direct laryngoscopy in the office prior to surgical intervention will give a baseline assessment of the vocal cords. These patients should ideally be referred to COEs and treated by experienced multidisciplinary teams for optimal treatment.

Children diagnosed with papillary thyroid cancer should undergo total thyroidectomy due to an increased incidence of multifocal and bilateral disease (see Fig. 72.3 ). If a total thyroidectomy is not performed, there is an increased risk of recurrence or the need for more operations. ^{, ,} The ATA recommends performing a central lymph neck dissection (CLND) in children with clinical evidence of invasion outside the thyroid gland, and/or if locoregional metastases are found either intraoperatively or on preoperative imaging, as there is an increased disease-free survival with CLND in these children. In children without these findings, CLND should be considered based on whether the disease is focal or more diffuse, the size of the tumor, and the surgeon’s experience. In children with unifocal disease, ipsilateral CLND can be considered. The neck dissection should be complete and compartment based, not based on cherry-picking or palpation. The ATA guidelines do not recommend routine lateral neck dissections, but indicate it should be performed on patients with positive FNA of clinically or radiographically suspicious lymph nodes in the lateral neck. Postoperative staging and surveillance is dependent on the ATA Pediatric Thyroid Cancer Risk Levels, which are derived from the American Joint Commission for Cancer TNM classification system, and stratifies patients as low risk, intermediate risk, or high risk. Staging is usually performed within 12 weeks after resection and allows for stratification of patients who may benefit from further resection or ¹³¹ I therapy. It usually includes I diagnostic whole body scans (except for ATA pediatric low-risk patients), TSH-stimulated thyroglobulin, and may include neck US or positron emission tomography(PET)/computed tomography (CT). ¹³¹ I therapy is indicated for the treatment of nodal or other locoregional disease that cannot be resected, as well as distant metastases. ^, Neck US surveillance should be performed 6 months postoperatively, and then annually for ATA low-risk children, and on a 6- to 12-month basis for ATA intermediate and high-risk children. Surveillance should be continued for at least 5 years.

In the past, the reported incidence of recurrent laryngeal nerve injury has ranged from 0% to 24%, and permanent hypocalcemia has been found in 6%–27% of patients undergoing total thyroidectomy. ^, A more contemporary study reports a permanent recurrent laryngeal nerve injury rate of 1.1% and a permanent hypocalcemia rate of 1.1%. The most reliable way to preserve parathyroid gland function is to identify and preserve the glands at the time of thyroidectomy ( Fig. 72.4 ). If there is apparent devascularization at the time of thyroid resection, then one or two of the glands should be auto-transplanted into the sternocleidomastoid muscle or the nondominant forearm. Near infrared autofluorescence is an emerging technology being investigated and used for intraoperative parathyroid gland evaluation and may be able to identify healthy and diseased parathyroid glands with up to 97% accuracy. The utility in pediatrics has not yet been determined definitively. During dissection, the laryngeal nerve should be identified and protected (see Fig. 72.4 ). Intraoperative neural monitoring can help avoid recurrent laryngeal nerve injury and allows for assessment of intraoperative nerve function. When the tumor invades the laryngeal nerve, the nerve and a rim of tumor can be safely preserved without compromising survival using adjuvant therapy with ¹³¹ I therapy to eradicate any residual tumor.

The relationship of the parathyroid glands to the recurrent laryngeal nerve during prophylactic thyroidectomy for MEN type 2 is seen. The left recurrent laryngeal nerve is marked by an asterisk. The superior parathyroid gland (arrowhead) is typically located posterior to the nerve. The inferior parathyroid gland (arrow) is usually found anterior to the nerve.

Pulmonary metastases are found in about 6% of children at the time of diagnosis, but they rarely develop in the absence of significant cervical lymph node metastases. ^, Pulmonary metastases require treatment with radioiodine. Plain chest films demonstrate the pulmonary disease in only 60% of cases, making scanning with radioiodine necessary. The pulmonary scintiscan can be falsely negative if there is significant residual thyroid tissue in the neck.

Follicular thyroid cancer in children is rare. Less than 10% of thyroid cancer in children is follicular, and the prevalence seems to be decreasing. ^{, ,} Due to its rarity, it is poorly studied, and therefore, management is more debatable. The ATA recommends total thyroidectomy for patients with clear vascular invasion, known distant metastases, or tumor size >4 cm. Minimally invasive follicular thyroid cancer with minimal or no vascular invasion (three or fewer vessels involved) can be treated with lobectomy and ¹³¹ I therapy, but treatment should be decided on a case-by-case basis. Children with follicular thyroid cancer should be considered for genetic counseling and genetic testing for germline PTEN mutations. The PTEN gene encodes for the Phosphatase and TENsin homolog protein, a tumor suppressor gene.

Medullary thyroid cancer (MTC) accounts for approximately 1%–2% of thyroid cancers in the United States, and 5% of pediatric thyroid neoplasms. Arising from the parafollicular C cells, MTC occurs either sporadically or in association with MEN 2A, or 2B, or the FMTC (Familial Medullary Thyroid Carcinoma) syndrome. MTC is usually the first tumor to develop in patients with the MEN syndrome and is the most common cause of death in this group. The neoplasm is particularly virulent in patients with MEN 2B and can even occur in infancy.

In the setting of nonfamilial MTC, the diagnosis is usually made only after metastatic spread of the tumor has occurred to the adjacent cervical lymph nodes or to distant sites. Resection is the only effective treatment for MTC, underscoring the importance of early diagnosis and therapy before metastases occur. Recently revised ATA management guidelines for MTC do not differentiate between adults and children except for the role of prophylactic thyroidectomy. Therefore, a child with an FNA diagnosis of MTC should undergo a complete US of the neck with a high-resolution probe and Doppler evaluation, similar to papillary thyroid carcinoma. Serum levels of calcitonin and carcinoembryonic antigen (CEA) should be checked, as well as DNA analysis for RET germline mutation ( Fig. 72.5 ). If the child is RET positive, they should be evaluated for a pheochromocytoma and hyperparathyroidism ( Fig. 72.6 ). If a pheochromocytoma is present, an adrenalectomy should be performed prior to thyroidectomy. If hyperparathyroidism is present, it can be treated at the time of the thyroidectomy.

The management of patients with a thyroid nodule and the histologic diagnosis of medullary thyroid carcinoma is shown. ADX, adrenalectomy; CEA, carcinoembryonic antigen; Ctn, calcitonin; EBRT, external beam radiotherapy; FNA, fine-needle aspiration; HPTH, hyperparathyroidism; LND, lymph node dissection; M, metastatic MTC; MTC, medullary thyroid carcinoma; PHEO, pheochromocytoma; RET , REarranged during Transfection; TKI, tyrosine kinase inhibitor; TTX, total thyroidectomy; US, ultrasound.

From Wells SA, Asa SL, Dralle H, et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015; 25:567–610. Used with the permission of Mary Ann Liebert, Inc. publishers.

The management of patients with RET germline mutation detected on genetic screening is depicted. ATA, American Thyroid Association risk categories for aggressive medullary thyroid cancer (MTC) (HST, highest risk, H, high risk, MOD, moderate risk); Ctn, calcitonin; CEA, carcinoembryonic antigen, HPTH, hyperparathyroidism; PHEO, pheochromocytoma; RET , REarranged during Transfection; TTX, total thyroidectomy; US, ultrasound.

From Wells SA, Asa SL, Dralle H et al. Revised American Thyroid Association guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015; 25:567–610. Used with the permission of Mary Ann Liebert, Inc. publishers.

The calcitonin levels and the US findings help determine the need for a lateral neck dissection at the time of thyroidectomy. For patients with a calcitonin <500 pg/mL and no suspicious US findings in the lateral neck, total thyroidectomy and central neck dissection are performed. However, if there are US findings of suspicious nodes in the lateral neck, then a lateral lymph node dissection should also be performed. For patients with calcitonin >500 pg/mL and/or those with extensive neck disease, metastatic workup should ensue (including CT neck, chest, and abdomen), with total thyroidectomy reserved for patients without metastatic disease. External beam radiotherapy is a consideration for patients with extensive disease, residual disease, or extrathyroidal extension.

Since MTC in children often presents after metastatic spread has occurred, optimal management of MTC from MEN 2 and FMTC kindreds relies on the presymptomatic detection of the RET proto-oncogene mutation responsible for the disease using screening tests. In young and asymptomatic MEN 2A kindred patients found to have the RET proto-oncogene mutation during screening, prophylactic thyroidectomy has been shown to prevent or cure MTC. In one study, 66% of children and teenagers with the RET proto-oncogene mutation already had foci of MCT within the thyroid gland at the time of their prophylactic thyroidectomy. However, no child younger than 8 years of age was found to have metastatic disease at the time of operation. Moreover, when followed for 5–8 years, none of these patients had evidence of persistent or recurrent disease. It is therefore recommended that affected children with MEN 2A who are ATA high risk undergo total thyroidectomy prior to age 5 years, and those that are ATA moderate risk undergo total thyroidectomy when the serum calcitonin level becomes elevated (see Fig. 72.6 ). ATA risk stratification is based on particular RET mutations.

Prophylactic thyroidectomy should be performed at approximately 1 year of age in children with MEN 2B because of the increased virulence of MTC in this population. CLND, with removal of lymph nodes medial to the carotid sheaths and between the hyoid bone and the sternum is recommended. However, in very young children, identification of the parathyroid glands can be very difficult, and consideration should be given to performing CLND only if the parathyroid glands can be identified and preserved or transplanted. Early detection of the MTC by DNA mutation analysis and early operative intervention result in a normal life expectancy.

Primary hyperparathyroidism in childhood most commonly arises from a solitary hyperfunctioning adenoma and rarely from diffuse hyperplasia of all four glands. Very rarely, it can be secondary to parathyroid carcinoma. In all these cases, the parathyroid gland escapes its homeostatic negative feedback loop, and the uncontrolled production of PTH results in hypercalcemia. These lesions are asymptomatic in fewer than 20% of children and can present with bone pain, osteoporosis and susceptibility to fractures, renal calculi, and even arrhythmias that may be fatal, as well as the neurologic manifestations of hypercalcemia . Primary hyperparathyroidism is more likely to present with end-organ damage in children than in adults. The typical presentation is between 6 years of age and adolescence; however, neonatal severe hyperparathyroidism (NSHPT) is a rare, life-threatening condition that affects infants and is due to inactivating mutations in the calcium-sensing receptor (CaSR) gene (discussed below). Hyperparathyroidism is also associated with the MEN syndromes. Hyperplasia in all four glands is a feature of MEN 1, but also develops in approximately 30% of MEN 2A patients by their second or third decade of life. ^, The parathyroid glands can be identified and autotransplanted into the nondominant forearm at the time of prophylactic thyroidectomy for MEN 2. This provides easy access for removal of the heterotopic tissue, in case hyperparathyroidism develops later.

Operative treatment is the mainstay of the management of primary hyperparathyroidism in children. A solitary hyperfunctioning adenoma accounts for the majority of primary hyperparathyroidism ( Fig. 72.7 ). This is treated safely and effectively with a unilateral neck exploration when preoperative studies demonstrate a single abnormal gland. ^, Accurate preoperative localization studies (US, sestamibi scans, ± CT/magnetic resonance imaging [MRI]) and rapid intraoperative PTH (IO-PTH) assays are a necessary prerequisite for unilateral neck exploration and minimally invasive parathyroidectomy (MIP) via small incisions. ^99m Tc-sestamibi is avidly taken up by parathyroid tissue, especially adenomas ( Fig. 72.8 ). The sensitivity of detecting abnormal parathyroid glands by sestamibi scan alone is improved with dual modality imaging in conjunction with US or single-photon emission computerized tomography (SPECT-CT). US and sestamibi scan in concordance can localize adenomas in 44% of cases and conclusively differentiate between four-gland hyperplasia and single adenoma 100% of the time. ^, Newer technologies for preoperative parathyroid localization include “4-dimensional” CT scan (4D CT) and “4-dimensional” magnetic resonance imaging (4D-MRI). These are newer technologies that are still in evolution. The biggest drawback of 4D CT is the increased radiation dose, which limits its use as a primary imaging modality in pediatric patients . However, it may be considered in patients with bulky tumors or previous neck explorations.

This intraoperative photograph demonstrates an enlarged right superior parathyroid adenoma (arrow) during unilateral neck exploration that was directed by preoperative localizing studies.

Early and delayed ^99m Tc-sestamibi scintigraphy in a 12-year-old boy with primary hyperparathyroidism. (A) The image at 15 minutes demonstrates rapid uptake of the radioisotope by the thyroid gland (arrow) . (B) The image at 2 hours reveals that the radioisotope has been washed out of the thyroid, but a focus persists (arrow) that is consistent with a right parathyroid adenoma.

Minimally invasive parathyroidectomy can be done with either a small incision overlying the affected gland or through a small primary collar incision. Use of IO-PTH confirms that the affected gland(s) is excised. After resection of the abnormal parathyroid gland, a baseline serum PTH level is obtained, followed by PTH levels drawn at 5 and 10 minutes. As the intact PTH half-life is short, a >50% drop in intraoperative PTH level within 10 minutes signifies successful excision of the hyperfunctioning parathyroid tissue ( Fig. 72.9 ). This use of IO-PTH is especially useful in limiting exploration and predicting cure when preoperative imaging studies are not conclusive.

A rapid intraoperative parathyroid hormone (IOPTH) assay during unilateral focused parathyroidectomy is depicted. Baseline plasma PTH levels have been drawn. Time 0 represents the moment of resection of the hypersecreting parathyroid gland. PTH levels are drawn at 5 and 10 minutes. A 50% decline in PTH level from baseline at 10 minutes indicates that the offending parathyroid gland or glands have been removed.

Neck exploration with evaluation of all four parathyroid glands is traditionally the standard parathyroid operation and should be employed if the patient has an inappropriate IO-PTH response with single gland excision, a single lesion is not identified either on preoperative imaging or intraoperatively, with parathyroid gland hyperplasia, or in suspected MEN syndromes. It is also important to note that there is a high incidence of ectopic parathyroid gland location in children and adolescents with primary hyperparathyroidism, which may also necessitate four-gland exploration. In patients with parathyroid hyperplasia involving all of the glands, operative management can include 3½ gland parathyroidectomy or total parathyroidectomy with heterotopic autotransplantation of some parathyroid tissue back into the sternocleidomastoid or nondominant forearm. ^, Both approaches are safe in infants and children, and the latter has the advantage of avoiding repeated neck exploration if hyperparathyroidism should recur. ^, Moreover, the latter also results in improved survival in infants with severe hypercalcemia. There is a risk of recurrence with this approach compared to four-gland parathyroidectomy, with reported recurrence of 6%–12%, most often associated with familial hyperparathyroidism.

Parathyroid carcinoma as a cause of hypercalcemia in pediatric patients is exceedingly rare. Only approximately 20 cases are described in the literature ^{, ,} ; only 1% of all cases of primary hyperparathyroidism are due to parathyroid carcinoma, and most are in adults. Therefore, recommendations regarding treatment are based on adult management guidelines. Significant hypercalcemia or recurrent primary hyperparathyroidism may be an indicator of parathyroid carcinoma, but this diagnosis is made upon pathologic and histologic evaluation.

Neonatal severe hyperparathyroidism is a unique type of pediatric hyperparathyroidism. It is associated with a mutation in the calcium-sensing receptor genes resulting in inactivation. These neonates have parathyroid hyperplasia, unopposed PTH secretion, and severe hypercalcemia. The severity of hypercalcemia and symptomatic presentation is variable and related to the particular mutation the child has and whether they have a homozygous or heterozygous inheritance pattern with the homozygous being significantly more severe. The initial presentation in the immediate newborn period is failure to thrive, hypotonia, respiratory distress, and hypercalcemia often >20 mg/dL. Severe and untreated cases can result in devastating neurological deficits or even death. These infants benefit from parathyroidectomy with transplantation of one or half a gland and were traditionally managed this way, but newer literature supports the use of potent intravenous bisphosphonates. ^, Patients with the homozygous mutation may be refractory to medical management and require surgical excision. This entity must be differentiated from transient neonatal hyperparathyroidism that occurs secondary to maternal hypocalcemia.

Familial hypocalciuric hypercalcemia is an inherited autosomal dominant disorder caused by a heterozygous mutation in the Ca ²⁺ -sensing receptor (CASR) gene, resulting in a relatively asymptomatic form of neonatal severe hyperparathyroidism. ^, It differs from primary hyperparathyroidism in that the PTH value is normal but urinary excretion of calcium is low. Patients are usually asymptomatic with an elevated serum calcium level. This disorder can usually be managed medically.

Secondary hyperparathyroidism occurs in children with renal insufficiency resulting in reduced renal vitamin D activation and therefore decreased GI absorption of calcium. It can also be seen in children with malabsorption. Hypocalcemia is worsened due to a reduced renal excretion of phosphate and the resulting excess serum phosphate binding to calcium, which decreases active calcium levels in the serum. The resulting hypocalcemia triggers PTH production, which in turn chronically overstimulates the parathyroid glands and causes four-gland hyperplasia. Medical treatment focuses on decreasing intestinal phosphorus absorption, and patients typically respond well. In rare cases, severe renal osteodystrophy can result in skeletal fractures and metastatic calcifications. These markedly severe cases of secondary hyperparathyroidism may benefit from total parathyroidectomy with autotransplantation.

Tertiary hyperparathyroidism occurs when the parathyroid glands are exposed to prolonged stimulation from long-term hypocalcemia and begin autonomous PTH production, even after the inciting stimulus has been removed. After the calcium levels rise to normal or higher, the glands continue autonomous PTH production because they have lost their response to the negative feedback loop. This can be seen in chronic renal failure patients and a very small percentage of secondary hyperparathyroidism patients who undergo renal transplantation. As tertiary hyperparathyroidism is commonly due to hyperplasia of all four glands, these children should be offered total parathyroidectomy with autotransplantation, after allowing enough delay for potential spontaneous regression of glandular hyperplasia.

Extracellular fluid volume, sodium, and potassium balance are regulated by aldosterone, which in turn is released in response to the renin–angiotensin system. The juxtaglomerular cells in the kidney secrete renin as a response to decreased pressure in the renal afferent arterioles and decreased plasma concentration detected by the macula densa. Renin converts angiotensinogen into angiotensin I in the liver, which is subsequently converted to angiotensin II by the angiotensin converting enzyme in the lung. Angiotensin II is a potent vasoconstrictor and causes release of aldosterone by directly stimulating the zona glomerulosa. The renal tubular reabsorption of sodium in exchange for potassium and hydrogen is then upregulated by aldosterone, resulting in increased renal fluid resorption and expanded intravascular volume.

Cortisol-releasing factor (CRF) is released by the hypothalamus and is responsible for cortisol regulation. CRF stimulates pituitary release of adrenocorticotropic hormone (ACTH). Cortisol has far-reaching physiologic effects including stimulation of hepatic gluconeogenesis, inhibition of protein synthesis, increased protein catabolism, and lipolysis of adipose tissue. Negative effects of cortisol include loss of collagen, decreased fibroblast activity resulting in inhibition of wound healing, and induction of a negative calcium balance leading to osteoporosis.

Adrenal androgens include dehydroepiandrosterone (DHEA) and DHEA sulfate (DHEA-S). After systemic release by the adrenal gland, these hormones are converted to the biologically active forms testosterone and dihydrotestosterone. Adrenal androgens account for <5% of the circulating testosterone in typical males, and therefore often have a clinically negligible effect. However, in the setting of congenital adrenal hyperplasia (CAH), steroid precursors that would usually be converted to cortisol and/or aldosterone are shuttled into the androgen synthesis pathway, resulting in excess androgens and the associated clinical virilization. This is due to a group of autosomal recessive enzyme deficiencies, the most common being a deficiency in the enzyme 21-hydroxylase, which accounts for >90% of CAH.

Hypercortisolism, or Cushing syndrome, results from systemic glucocorticoid excess. It can be caused by ACTH secreting pituitary adenomas, hormonally active adrenal tumors including carcinoma and adenoma, ectopic ACTH syndrome, nodular adrenal hyperplasia, and ACTH-producing tumors ( Box 72.4 ). Additionally, iatrogenic Cushing syndrome is the most common cause of hypercortisolism in adults and children and is due to exogenous administration of supraphysiologic amounts of ACTH or glucocorticoids over a prolonged time period. On the other hand, Cushing disease is caused by a pituitary adenoma, which is the second most common cause of Cushing syndrome in children. Tumors that can produce ACTH are rare in children and include pulmonary neoplasms, neuroblastomas, pancreatic islet cell carcinomas, thymomas, carcinoids, MTCs, and pheochromocytomas. In children, ectopic ACTH is most commonly due to a bronchial carcinoid, with presenting ACTH levels usually 10–100 times higher than in Cushing disease. Such significantly elevated levels of ACTH result in hypokalemic alkalosis. Hypercortisolism can also be due to ACTH-independent multinodular adrenal hyperplasia, which is characterized by hypersecretion of both cortisol and adrenal androgens.

Hypercortisolism is more common in children than previously recognized. The most common cause of Cushing syndrome in children younger than 7 years of age is an adrenal tumor ( Fig. 72.11 ). In those older than 7 years, adrenal hyperplasia secondary to hypersecretion of pituitary ACTH is most common.

This 8-month-old child was seen in the emergency department for progressive facial swelling. (A) Examination reveals cushingoid features with moon facies. In addition, she had generalized obesity. Her plasma cortisol level was elevated, and her ACTH level was suppressed. (B) CT scan revealed a 4.3 cm × 4.8 × 4.8 cm left adrenal mass that was homogeneous and showed no evidence of invasion of adjacent structures. The infant subsequently underwent laparoscopic left adrenalectomy and was discharged on postoperative day 2. (C) At 2-month follow-up, there was marked improvement in the physical manifestations of her Cushing syndrome.

From Kim E, Aguayo P, St. Peter SD et al. Adrenocortical adenoma expressing glucocorticoid in an 8-month-old female. Eur J Pediatr Surg. 2008; 18:1–2.

The clinical features of Cushing syndrome can take 5 years or longer to develop. Thus, the classic Cushingoid appearance may not be seen in children. Weight gain and growth failure are the most common and the most reliable findings. Therefore, any obese child who stops growing should be evaluated for Cushing syndrome, which consists of laboratory screening followed by localization if the labs suggest a source. ^, Laboratory evaluation involves measuring the plasma cortisol to coincide with the diurnal variation: at 8:00 a.m. (normal levels, <14 mg/dL) and 6:00 p.m. (normal levels, <8 mg/dL). The loss of diurnal rhythm is usually the earliest laboratory evidence of Cushing disease. A single measurement at midnight should be < 2 mg/dL in normal patients and >2 mg/dL in patients with Cushing disease. The 24-hour urinary 17-hydroxycorticosteroid or free cortisol value is the most sensitive screening test and is > 150 mg/day in patients with Cushing syndrome. The overnight dexamethasone suppression test is performed by administering 1 mg of dexamethasone at 11:00 p.m. and measuring the plasma cortisol level the following morning at 8:00 a.m. ACTH is suppressed, and the cortisol level is decreased by 50% or more from baseline (<5 mg/dL) in normal individuals. However, in patients with Cushing syndrome, this is an insufficient dose to result in cortisol suppression.

After establishing a diagnosis of Cushing syndrome, the specific cause must be determined. ^, Pituitary causes are differentiated from nonpituitary causes with a high-dose dexamethasone suppression test. An oral dose of 2 mg of dexamethasone is given every 6 hours for 48 hours (or 40 mg/kg/dose for infants). Urine is then collected for 24 hours to measure free cortisol and 17-hydroxysteroids. A primary pituitary neoplasm will have the steroid excretion levels suppressed to 50% of baseline. In the setting of an adrenal adenoma, adrenocortical carcinoma, or ACTH-producing tumors, levels are not suppressed. Plasma ACTH levels are generally low or normal with adrenal causes of hypercortisolism, modestly elevated with pituitary neoplasms, and extremely elevated with tumors producing ectopic ACTH.

More than 90% of children with Cushing disease have a surgically identifiable microadenoma for which transsphenoidal hypophysectomy is indicated. After complete resection, 20% of patients will often undergo a second transsphenoidal resection. If this also fails, adrenalectomy is needed. Pituitary irradiation, adrenalectomy, and drugs inhibiting adrenal function are alternate therapies.

Excess adrenal production of aldosterone with consequent suppression of renin and angiotensin causes primary hyperaldosteronism. Adrenocortical hyperplasia is the most common cause in children, but an adrenal adenoma, or Conn syndrome, is the most common cause of primary hyperaldosteronism in adults. Rarely, an adrenal carcinoma can present as primary hyperaldosteronism. MEN 1-related adrenal tumors can also result in primary hyperaldosteronism.

Signs and symptoms of primary hyperaldosteronism are generally nonspecific: hypertension, muscle weakness, polydipsia, and polyuria. Hyperaldosteronism increases total body sodium and consequently increases total body fluid resulting in hypertension and hypokalemic alkalosis. Therefore, evaluation for primary hyperaldosteronism is warranted in a child with these findings. A serum potassium level should be checked, and a level of <3.5 mEq/L is consistent with the diagnosis. On further serum analysis, the aldosterone level will be elevated, the renin level suppressed, and patients will frequently have a metabolic alkalosis. Confirmation consists of a saline load challenge. In normal subjects, the saline bolus will decrease plasma aldosterone levels below 6–8 ng/dL. An abnormal response will show no decrease of plasma aldosterone. This can also be done as an outpatient by administering a high-sodium diet for 3–5 days. A failure of aldosterone suppression indicates hyperaldosteronism. The serum aldosterone level should be drawn in the morning before the patient has assumed an upright position.

Once the diagnosis of hyperaldosteronism is made, delineating between an aldosterone-secreting adenoma or bilateral adrenal hyperplasia is the next step. This is done via MRI or CT. An adenoma is diagnosed on imaging when a solitary adrenal mass >1 cm is found with a normal-appearing contralateral gland. When imaging is inconclusive, selective adrenal vein sampling can differentiate unilateral versus bilateral aldosterone hypersecretion. An alternate diagnostic modality is scintigraphy with ¹³¹ I-iodomethylnorcholesterol (NP-59), a cholesterol analog taken up as cholesterol in the steroidogenic pathway. Dexamethasone suppression of ACTH-dependent adrenocortical tissue is followed by NP-59 administration. If the resulting adrenal uptake is symmetric, bilateral hyperplasia is suggested, whereas asymmetric uptake indicates an adenoma. A functioning adrenal adenoma should be resected and is usually approached laparoscopically. ^{, ,} Robotic adrenalectomy is also becoming an approach to consider in centers with robust experience with robotic surgery for children. Bilateral adrenal hyperplasia is treated with spironolactone.

Adrenocortical carcinoma is rare in children with an incidence of 1–1.5 per million population per year, with peak incidences in childhood and in the fifth decade of life. These tumors are more common in females (2:1), have equal distribution in the left and right sides, and are hormonally functional in 80%–100% of patients. While adrenocortical carcinoma (ACC) is rare in children, it should be noted that only 10%–20% of functional tumors in children are benign adenomas. About 50% occur in children <5 years old. There is geographic variability, with southern Brazil having a 15-fold greater incidence compared with other countries due to a unique p53 germline mutation.

The etiology of adrenocortical carcinoma is unknown, but it is associated with several hereditary tumor syndromes, which gives insight into the molecular pathogenesis. Often pediatric cases of ACC are associated with cancer predisposition syndromes. Germline mutations in the p53 tumor suppressor gene on chromosome 17p13.1 are found in 70% of families affected by Li–Fraumeni syndrome. These mutations have also been found in 20%–30% of sporadic cases of adrenocortical carcinomas. Beckwith–Wiedemann syndrome predisposes to adrenocortical carcinoma in addition to other tumors, with overexpression of insulin-like growth factor (IGF)-2 believed to contribute to the tumorigenesis. Several genetic alterations resulting in IGF-2 overexpression have been demonstrated in the majority of adrenocortical carcinomas. ^{, ,} Carney complex, MEN 1, and CAH are other hereditary syndromes associated with adrenocortical tumors, ^, but these are mostly adenomas and rarely carcinoma. Most of the molecular work for adrenocortical carcinoma has focused on adults, but investigators have started to evaluate gene expression profiles in children and have found similarities to the adult population. Additionally, transcriptomes, which are the sum total of all the messenger RNA molecules expressed by a tumor, can help discriminate between adrenocortical adenomas and carcinomas, as well as identify subgroups of carcinomas with different prognoses.

Patients with adrenocortical carcinoma usually present with steroid overproduction. In contrast to adult tumors, most pediatric adrenocortical tumors are hormonally active. Most present with features of virilization (66%), and the rest show symptoms of Cushing syndrome. ^, Virilization is secondary to secretion of the adrenal androgens with development of axillary and pubic hair, deepening of the voice, acne, rapid height growth, hirsutism, enlargement of the penis or clitoromegaly, and development of body odor. Feminization may occur in 2%–25% of patients from an overproduction of estrogens, particularly estradiol. Only about 5%–10% of pediatric adrenocortical cancers produce no clinical evidence of hormone excess, and these are typically found in adolescents.

Virilization warrants chemical evaluation including measurements of plasma testosterone and urinary and plasma DHEA and DHEA-S. Measurement of urinary 17-ketosteroids is necessary as two-thirds of 17-ketosteroids are derived from adrenal androgens. Although the most specific assessment of adrenal androgen production is DHEA-S, 17-ketosteroids are more frequently elevated in malignant disease. ^, The clinical presentation of Cushing syndrome is confirmed by the laboratory tests discussed previously. Significantly greater elevations of 17-hydroxycorticosteroids and plasma cortisol are generally seen with malignant disease than with functioning adenomas.

Radiographic imaging should occur concurrently with the laboratory workup so that surgical intervention is not delayed. US can be used for the initial screening evaluation and also for postoperative assessment of recurrence. Smaller lesions are smooth and homogeneous with no pattern of hyperechogenicity or hypoechogenicity. Larger lesions usually demonstrate a “scar sign,” which consists of radiating linear echoes representing an interphase between separate areas of necrosis, hemorrhage, and neoplasm. ^, CT detects tumors as small as 0.5 cm and can identify regional invasion, distant metastases in the liver, lung, or brain, and vascular involvement ( Fig. 72.12 ). Unlike in the adult population, there are no washout thresholds to indicate benign versus malignant lesions in children. MRI has an accuracy similar to CT with lesions larger than 1–2 cm and is ever improving, but again lacking criteria regarding drop of signal on out-of-phase MRI to determine malignant potential as compared to the adult population. In comparison to adrenal venous sampling, both CT and MRI are not very accurate in predicting unilateral disease. However, in children, adrenal venous sampling is considered unnecessary and too invasive. MRI has the added benefit of avoiding radiation exposure. Finally, adrenal scintigraphy using iodocholesterol-labeled analogs has shown promise in identifying and differentiating functional adrenal lesions, although it carries the added risk of radiation exposure. FDG-PET/CT may also be useful in determining malignant potential of lesions.

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