Endocrine Tumors
Steven G. Waguespack
Winston W. Huh
Andrew J. Bauer
INTRODUCTION
Endocrine tumors comprise a variety of benign and malignant neoplasms that arise from the endocrine glands or neuroendocrine tissues. Functioning tumors are associated with typical clinical syndromes related to the specific hormone(s) being secreted, whereas nonfunctioning tumors present incidentally or secondary to symptoms related to mass effect. While most childhood endocrine tumors are sporadic without an identifiable mutation in germline DNA, others are familial, such as those that occur as part of the multiple endocrine neoplasia (MEN) syndromes. Endocrine tumors represent a minority of all neoplasms observed in the pediatric population and are generally clinically benign or low-grade cancers, although a small percentage of these tumors are high-grade malignancies requiring multimodality therapies. As with any rare childhood disease, treatment is best provided at tertiary care centers with multidisciplinary expertise in the management of such tumors.
PITUITARY TUMORS
Pituitary Adenomas
Epidemiology and Pathophysiology
The differential diagnosis for a pediatric sellar/suprasellar mass is broad.1 A pituitary adenoma (PA) is a benign monoclonal neoplasm that arises from the anterior pituitary gland (adenohypophysis). PAs represent about 1.6% to 2.7% of all supratentorial tumors diagnosed during childhood, and 2% to 6% of all pituitary tumors treated surgically are in children.2,3 Pubertal children represent the largest group, with over 75% of PAs occurring in children older than 12 years, and females are more commonly affected than males. During adolescence and in patients with profound primary endocrine gland dysfunction (e.g., severe primary hypothyroidism), the pituitary may undergo significant hyperplasia and falsely resemble a neoplasm. Pituitary hyperplasia and clinical syndromes of hormone excess can also rarely occur secondary to ectopic secretion of the hypothalamic hormones corticotropin-releasing hormone (CRH) and growth hormone-releasing hormone (GHRH). Tumors that metastasize to the pituitary gland are exceedingly rare in the pediatric population.
PA development is primarily driven by a combination of genetic, physiologic, and environmental factors. Genetic syndromes associated with PAs include MEN1, MEN4, familial isolated PAs (FIPA), familial paraganglioma syndromes, Carney complex (CNC), the tuberous sclerosis complex (TSC), and the McCune-Albright syndrome (MAS)4,5,6,7 (Table 36.1).
Clinical Presentation and Diagnosis
Pituitary tumors are usually diagnosed secondary to symptoms of hormone excess or mass effect, such as visual disturbance (classically a bitemporal hemianopsia), headache, or ophthalmoplegia. Children may also present with delayed growth and/or delayed puberty due to pituitary hormone hypersecretion, as seen with hyperprolactinemia, or hyposecretion, as seen with large PAs that compress the normal adenohypophyseal tissue. The incidental identification of PAs is becoming more commonplace. Pituitary apoplexy (infarction and/or hemorrhage into a preexisting tumor) can also be the presenting feature of a PA, but central diabetes insipidus is not typical in the clinical presentation of a benign or noninfiltrative sellar mass.2
Pituitary tumors can be plurihormonal, secreting more than one hormone, most commonly a combination of growth hormone (GH) and prolactin (PRL).2 Although the clinical and biochemical phenotype of a functioning PA generally correlates with immunohistochemical findings, this is not always the case, and immunohistochemistry alone does not make the diagnosis of a functional tumor.
In a child with a PA, the initial workup includes imaging of the sella turcica, a comprehensive hormonal evaluation to assess for hyper- and hypopituitarism, and visual field testing for children with large tumors that compress the optic chiasm. The best imaging modality for the diagnosis of PAs is T1-weighted spin-echo magnetic resonance imaging (MRI) of the pituitary in both coronal and sagittal planes (obtained at 3-mm intervals) before and after the intravenous administration of gadolinium (Fig. 36.1). Pituitary microadenomas, such as those that cause Cushing disease (CD), may be better identified via dynamic contrast-enhanced MRI.8 High-resolution computerized tomography can be useful in the identification of calcifications (pathognomonic for craniopharyngioma) and in those patients who otherwise cannot get an MRI. Microadenomas are defined as PAs ≤1 cm in greatest dimension, whereas macroadenomas are >1 cm (Fig. 36.1); the rare tumor that exceeds 4 cm is termed a giant adenoma.
Staging and Prognosis
PAs are classified by the World Health Organization (WHO) into typical PAs, atypical PAs, and pituitary carcinomas. Atypical PAs are nonmetastatic tumors with morphologic features suggestive of aggressive behavior, including extensive nuclear staining for p53, an elevated mitotic index, and Ki-67 labeling index >3%.9 PAs may be locally invasive (Fig. 36.1), but an invasive growth pattern does not necessarily portend a more dire clinical course. In pediatric patients with non-adrenocorticotropin hormone (ACTH)-secreting PAs, disease-free survival is lower for macroadenomas, and these children typically require more aggressive multimodality therapy and have higher rates of hypopituitarism.2 While the mortality for children with PAs is low, there may be significant morbidity due to surgical complications and/or hypopituitarism.
Treatment and Follow-Up
In general, transsphenoidal resection (TSR)7 is the treatment of choice for hormonally active tumors, with the notable exception of prolactinomas (see below). Surgery is also considered in macroadenomas causing mass effect or contributing to hypopituitarism, pituitary apoplexy, ineffectiveness or intolerance of medical therapy, and for smaller sellar masses associated with chronic severe headaches. In the right hands, TSR is a safe and effective procedure, and it is imperative to identify a high-volume pituitary neurosurgeon.10
TABLE 36.1 Genetic Syndromes Associated with Endocrine Neoplasia | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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 Figure 36.1 Various presentations of PAs on T1-weighted coronal MRI status post-gadolinium contrast. (A) Pituitary microadenoma (white arrow); (B) Pituitary macroadenoma (red asterisk); note the normal pituitary gland and pituitary stalk (red arrows) deviated to the right; (C) Invasive pituitary macroadenoma with extension through the right cavernous sinus into the right middle cranial fossa (white arrows); (D) Pituitary carcinoma with residual primary tumor (yellow arrow) and drop metastases (yellow asterisks). |
Microadenomas have a high surgical cure rate, whereas complete resection of pituitary macroadenomas is often not possible, particularly with tumors >2 cm and when cavernous sinus invasion and/or significant suprasellar extension is present. Radiation therapy has a limited role in the management of children with PAs, but is considered in uncontrolled functional tumors or unresectable nonfunctioning tumors that are progressive.7,11 Long-term follow-up should include periodic MRI and hormonal assessment based on the functional status of the PA and previous treatments required.
Late Effects/Complications of Treatment
Complications from surgery can include hypopituitarism, hemorrhage, transient or permanent diabetes insipidus, the syndrome of inappropriate antidiuretic hormone secretion, cerebrospinal fluid leak, and meningitis. Hypopituitarism arising from surgery is immediate, whereas hypopituitarism arising from radiation therapy is gradual and often insidious in its presentation, underscoring the need for long-term endocrine follow-up. Other late effects from radiation therapy can include visual deficits due to optic neuropathy, necrosis of normal brain tissue, second neoplasms (chiefly meningiomas and gliomas), cognitive impairment, and cerebrovascular disease.11
Pituitary Adenoma Subtypes
PRL-secreting Adenomas (Lactotroph Adenomas). Prolactinomas are the most common PA in childhood, representing at least 50% of cases, and they are diagnosed most commonly in postpubertal girls. Prepubertal children present with symptoms of mass effect and/or delayed puberty, whereas pubertal children can also present with oligo- or amenorrhea (girls), galactorrhea (both genders), and rarely gynecomastia (boys).12,13 Males are more likely to have macroadenomas and therefore tend to present with symptoms related to tumor size.2,12
The degree of hyperprolactinemia typically correlates with tumor size, and the diagnosis of a prolactinoma is highly likely when the PRL level is >250 ng/mL.14 In cases where the PRL level and clinical findings are discordant, the differential diagnosis includes hyperprolactinemia due to stalk compression, the presence of macroprolactinemia, and assay artifact secondary to the high-dose hook effect that can occur with macroprolactinomas and extremely elevated PRL levels.14 Patients with elevated PRL levels and no tumor on MRI should have an evaluation for secondary hyperprolactinemia. Primary hypothyroidism should always be ruled out as a cause of hyperprolactinemia and sellar mass. Because of the possibility of GH cosecretion, especially with tumor-predisposing genetic syndromes (Table 36.1), an insulin-like growth factor 1 (IGF-1) level should also be included in the initial evaluation.
Prolactinomas can effectively be treated with one of the available dopamine agonists (DAs), either bromocriptine or cabergoline, even in the presence of visual changes. Cabergoline is preferred due to its less-frequent administration, fewer side effects, and greater efficacy.14 Oral contraceptive pills are a reasonable alternative in adolescent girls with microadenomas and nonbothersome galactorrhea.15,16 Sex steroids can exacerbate PRL hypersecretion and promote tumor growth, so caution should be undertaken when prescribing testosterone or estrogen replacement to adolescents with macroprolactinomas. The addition of an aromatase inhibitor may facilitate the use of testosterone replacement in males.16
Clinical improvement is usually seen before radiologic tumor reduction. In most patients, treatment is continued until the PRL level normalizes (or at least stabilizes) and the tumor demonstrates significant shrinkage. Some patients will never achieve normal PRL levels, but many patients may ultimately be able to stop DA therapy.15,17
ACTH-secreting Adenomas (Corticotroph Adenoma; CD). ACTH-secreting adenomas causing CD are the second most common PA in children, occurring in approximately one-third of children operated on for a pituitary tumor.2,3 Corticotroph tumors are the most likely PA to be diagnosed in prepubertal children, and there is a female-to-male predominance, except in prepubertal children.18,19
The onset of symptoms is usually insidious, and most children have a typical Cushingoid phenotype (Fig. 36.2) with generalized weight gain, obesity, impairment of growth (in prepubertal patients), violaceous striae (chiefly in older children), hirsutism/premature pubarche, acne, and hypertension.18,20,21,22 Clinical presentation can also include rounding of the face (moon facies), plethora, abnormal fat distribution with increased fat deposition in the supraclavicular fossae and upper back (Buffalo hump), acanthosis nigricans, easy bruising, hyperpigmentation (with significant ACTH elevation), muscle weakness, edema, impaired glucose tolerance/diabetes mellitus, pubertal delay, emotional lability, fatigue, headache, menstrual disturbance, and low bone mass for age and fractures. Not every case of Cushing syndrome (CS) is classic, and the diagnosis can be hard to differentiate from exogenous obesity based on phenotype alone, as not all children with CS are short or have delayed bone ages as would be expected.18,20 One of the most sensitive indicators of possible CS in a growing child is weight gain associated with a low growth velocity.23
These tumors are usually microadenomas and are often not visualized on routine MRI.18,21 Because of that, the diagnosis of CD is not always straightforward and care must be taken to differentiate an ACTH-secreting PA from ectopic ACTH secretion, such as from a thymic or bronchial neuroendocrine tumor (NET).24 Fortunately the latter situation is rare in children.
The diagnostic studies for CS have not been extensively validated in children. Screening studies to make the diagnosis include measurement of 24-hour urine-free cortisol, the overnight 1 mg (low dose) dexamethasone (DEX) suppression test, the 2-day low-dose DEX suppression test, and assessment of impaired circadian rhythm through the measurement of late evening salivary or serum cortisol levels.18,23,25 The DEX/CRH test is utilized to distinguish CS from pseudo-CS states, although this test may not be as reliable in very obese children.26 Once the diagnosis of ACTH-dependent CS (i.e., ACTH levels not suppressed and generally >15 pg/mL) has been made, the source of ACTH can generally be attributed to the pituitary if a clear adenoma is identified. If MRI findings are negative or equivocal, it is necessary to undertake additional testing to differentiate a pituitary from a peripheral source of ACTH production. These tests can include an overnight 8-mg (high-dose) DEX suppression test, 2-day high-dose DEX suppression test, CRH test, CRH/desmopressin test, and CRH-stimulated inferior petrosal sinus sampling (IPSS).18,23 IPSS obtained at the time of hypercortisolism appears to be the most definitive diagnostic test in the workup of ACTH-dependent CS and is safe and useful in children at experienced centers. Although IPSS can confirm a central source of ACTH production, its use solely for tumor lateralization is questionable.
The medical management of CD includes the use of inhibitors of cortisol synthesis (etomidate, ketoconazole, metyrapone, mitotane [o, p′-DDD; rarely used in nonmalignant conditions]) or action (mifepristone) as well as agents that can directly inhibit tumoral production of ACTH (cabergoline, pasireotide).27,28 In the patient with CD who is not cured with surgery or radiotherapy and who continues to suffer from CS despite optimization of medical therapy, bilateral adrenalectomy is favored. Although patients are committed to life-long glucocorticoid and mineralocorticoid replacement, removal of all adrenocortical tissue is the best way to cure CS in the treatment-refractory patient. The development of Nelson syndrome (the association of an expanding pituitary tumor and a high ACTH concentration after adrenalectomy in patients with CD) is a theoretical concern in such children.29
GH-Secreting Adenomas (Somatotroph Adenomas; Gigantism/Acromegaly). Somatotroph adenomas are the third most common PA in childhood, have a higher prevalence in males, are usually macroadenomas, and represent about 8% of all cases and 0.63% of surgically treated pituitary tumors in children.3,30 Gigantism is the term used to describe the overgrowth that occurs because of GH excess in children with open epiphyses, whereas acromegaly describes GH excess occurring after epiphyseal closure. The clinical presentation is usually one of accelerating linear growth. Other common features include coarse facial features, frontal bossing, prognathism, and disproportionately large hands and feet with thick fingers and toes. Symptoms related to tumor mass effect, pubertal delay, and menstrual irregularities can also be present at diagnosis.30 Other signs and symptoms of GH excess that are more common in the patient with acromegaly are reviewed elsewhere.31
During early childhood, gigantism is typically caused by mammosomatotroph tumors, secreting both GH and PRL, underscoring the genetic basis of these tumors9 (Table 36.1). Sporadic adenomas can harbor somatic GNAS mutations in up to 40% of adult patients, but this is not generally seen in sporadic tumors identified in childhood.32
The best initial diagnostic test is measurement of an IGF-1 level, comparing it to age-matched normative ranges.33 Confirmatory testing is accomplished through a 1.75 g/kg (max 75 g) oral glucose tolerance test, during which GH levels should fall to <1 ng/mL (<0.4 ng/mL in sensitive assays) during the 2-hour testing period.33 The clinician must also consider the gender and pubertal status of the adolescent patient undergoing testing, as the nadir of GH after oral glucose ingestion may be higher than adults, especially in mid-pubertal girls.34
When surgery is not curative, pharmacologic inhibition of GH secretion and suppression of tumor growth are accomplished through the use of the somatostatin (SST) analogs (octreotide
and lanreotide) and/or the DA cabergoline.31,35 Pegvisomant, a competitive GH receptor antagonist that lowers IGF-1 levels but has no direct impact on tumor size, is another treatment alternative. Primary medical therapy can be considered in patients who have surgically incurable tumors that are not compromising vision and in patients who are not good candidates for or refuse surgery.
and lanreotide) and/or the DA cabergoline.31,35 Pegvisomant, a competitive GH receptor antagonist that lowers IGF-1 levels but has no direct impact on tumor size, is another treatment alternative. Primary medical therapy can be considered in patients who have surgically incurable tumors that are not compromising vision and in patients who are not good candidates for or refuse surgery.
 Figure 36.2 Signs of CS in three different patients. A: Typical appearance of CS with moon facies, acne, and abnormal fat distribution in the supraclavicular fossae. B: Central adiposity with classic violaceous wide striae. C: Thin extremities with easy bruising and thinning of the skin (Photo courtesy of Dr. Rachel Edelen). |
Clinically Nonfunctioning Adenomas (Null Cell Adenomas; Gonadotropin-secreting Adenomas). Clinically nonfunctioning tumors include those neoplasms that silently produce hormones (e.g., ACTH) without clinical signs or symptoms, in addition to those PAs that produce no pituitary hormones (null cell adenomas), bioinactive hormones, or hormones such as the gonadotropins (luteinizing and/or follicle-stimulating hormone) and α-subunit of the glycoprotein hormones that do not always cause clinical manifestations.9 In contradistinction to adults, these tumors represent <5% of pediatric PAs.2,3 Surgery is the mainstay of treatment, particularly in macroadenomas, which have a predisposition for enlargement and/or apoplexy over time.36 Medical management with a DA or SST analog can also be considered in the appropriate clinical setting but is typically ineffective.
Thyroid-stimulating Hormone-secreting Adenomas (Thyrotroph Adenomas). PAs secreting thyroid-stimulating hormone (TSH) are diagnosed because of elevated thyroxine and triiodothyronine levels and a nonsuppressed (and often elevated) TSH in the presence of a pituitary tumor on MRI. These tumors usually secrete excessive quantities of α-subunit, and the ratio of α-subunit to TSH is high, allowing for this diagnosis to be distinguished from pituitary resistance to thyroid hormone.37 Medical treatment includes SST analogs and DA, in addition to interventions directed at controlling the hyperthyroidism.
Pituitary Carcinoma
Epidemiology and Pathophysiology
Pituitary carcinomas are primary neoplasms of the adenohypophysis that arise from preexisting invasive adenomas after a variable latency period and that undergo craniospinal and/or systemic spread.38,39,40 Primary pituitary malignancies are exceedingly rare, representing only 0.2% of resected pituitary tumors.38 The diagnosis is almost always made in adulthood, but isolated pediatric case reports have been published.
Clinical Presentation and Diagnosis
The majority of pituitary carcinomas are functional tumors,38,40 and they present similarly to their benign counterparts; initial presentation with metastatic disease is rare. Sites of metastasis can include the brain, leptomeninges, liver, bones, lung, and lymph nodes. ACTH-secreting tumors are more likely to have systemic metastases, whereas PRL-secreting tumors tend to spread within the craniospinal axis.38 There is no single combination of histologic features in the primary tumor that is diagnostic for pituitary carcinoma, but early recurrence after initial surgery could suggest a possible malignancy.
Staging and Prognosis
The prognosis of pituitary carcinoma is poor.38,39,40 Mean survival is 2 years, although cases of prolonged survival have been documented.41 There is no formal staging system for this rare cancer.
Treatment
Treatment is primarily palliative in nature and should include a multidisciplinary approach utilizing surgery (sometimes with local instillation of chemotherapy-infused wafers), radiation therapy, medical therapy targeting hormonal hypersecretion, and systemic
antineoplastic treatments. Cytotoxic agents studied with variable success include lomustine and 5-fluorouracil (5-FU); carboplatin either as a single agent or combined with 5-FU or interferon α; cisplatin and etoposide; temozolomide ± capecitabine; and cyclophosphamide with doxorubicin in combination with either 5-FU or dacarbazine.40,42,43,44
antineoplastic treatments. Cytotoxic agents studied with variable success include lomustine and 5-fluorouracil (5-FU); carboplatin either as a single agent or combined with 5-FU or interferon α; cisplatin and etoposide; temozolomide ± capecitabine; and cyclophosphamide with doxorubicin in combination with either 5-FU or dacarbazine.40,42,43,44
PARATHYROID TUMORS
Parathyroid Adenomas/Hyperplasia
Epidemiology and Pathophysiology
Primary hyperparathyroidism (HPT) in children results from solitary parathyroid adenomas and multigland hyperplasia in about 80% and 16.5% of cases, respectively.45 The incidence of primary HPT in children is 2 to 5 per 100,000/y in children, and HPT is more common in older adolescents without a clear gender predilection.46 The only identified environmental risk factor is exposure of the head and neck to ionizing radiation.47 Familial syndromes (Table 36.1), chiefly MEN1, constitute as much as 30% to 50% of pediatric patients with primary HPT, compared with only 5% in adults.46,48 In all children presenting with parathyroid hormone (PTH)-mediated hypercalcemia, mutations in the calcium-sensing receptor (CaSR) should be considered. Familial hypocalciuric hypercalcemia (FHH), also called familial benign hypercalcemia, is secondary to loss-of-function mutations in the CaSR gene. These patients have biochemical characteristics similar to neoplastic causes of HPT and are distinguished by their relative hypocalciuria.49 As these patients do not have pathologic HPT, they do not require further treatment. Homozygotes or compound heterozygotes for mutations in the CaSR gene present at birth with severe neonatal HPT and will require intervention.
Clinical Presentation and Diagnosis
Symptoms of HPT in children can be nonspecific, including polyuria, fatigue, headache, poor appetite, weight loss, abdominal pain, nausea, and emesis. Children with primary HPT are likely to have more symptoms and higher calcium levels compared with adults.45,46,50 Because of delays in diagnosis, presenting features can also include nephrocalcinosis, nephrolithiasis, acute pancreatitis, band keratopathy, or bone involvement (brown tumors/osteitis fibrosa cystica in the most severe cases).
 Figure 36.3 Imaging of parathyroid tumors. A: Coronal (left) and sagittal (right) 4D CT of a sporadic parathyroid adenoma (green arrows). B: US imaging of the same tumor (green line) presented in (A). C: 99mTc-Sestamibi scan (left) with fused SPECT coronal images (right) identifying a profoundly hyperplastic parathyroid gland (white circle) in a patient with primary HPT and MEN1. |
The diagnosis of HPT is confirmed by demonstrating hypercalcemia and an inappropriately normal or high serum concentration of intact PTH in the absence of vitamin D deficiency. Phosphorus levels are often low and alkaline phosphatase levels can be elevated, with higher levels noted in HPT-induced bone disease.46 Twenty four-hour urine measurement of calcium and creatinine for calculation of the calcium clearance is necessary to rule out FHH. Bone radiographs may reveal characteristic lesions of osteitis fibrosa cystica and findings compatible with rickets. Assessment of bone density may demonstrate low bone mass for age. Imaging modalities used to localize parathyroid tumors include ultrasound (US), 99mTc-sestamibi scan with single photon emission computed tomography (SPECT) imaging, MRI, and high-resolution four-dimensional (4D) CT51(Fig. 36.3) although younger patients appear less likely to localize abnormal parathyroid glands on sestamibi scan or US.50 The sensitivity of 99mTc-sestamibi is reduced in the presence of multigland disease, a finding more common to patients with familial syndromes such as MEN1.
Treatment and Follow-Up
Treatment of HPT consists of surgical removal of the affected parathyroid gland(s). For all pediatric patients with primary HPT, but especially in situations where multigland disease is suspected, imaging is negative, or a second surgical exploration is needed, locating an experienced surgeon is of paramount importance.52,53 If preoperative localization studies identify a solitary adenoma, minimally invasive parathyroidectomy with the use of a rapid intraoperative PTH assay is generally the procedure of choice.54 In patients with genetic syndromes predisposing to multigland involvement, such as MEN1, possible surgical approaches include subtotal parathyroidectomy with viable remnant left in situ with a clip (the preferred approach in most centers) or total parathyroidectomy with forearm autograft.55,56 The appropriate timing
and indications for surgery in children with hereditary HPT have not yet been clearly defined. The medical management of hypercalcemia focuses on maintaining hydration, increasing urine calcium excretion, and diminishing bone resorption. Antiresorptive agents (bisphosphonates, subcutaneous calcitonin [CTN]) or the calcimimetic, cinacalcet, can also be used in the management of hypercalcemia in recalcitrant HPT or as a bridge to definitive surgical therapy.
and indications for surgery in children with hereditary HPT have not yet been clearly defined. The medical management of hypercalcemia focuses on maintaining hydration, increasing urine calcium excretion, and diminishing bone resorption. Antiresorptive agents (bisphosphonates, subcutaneous calcitonin [CTN]) or the calcimimetic, cinacalcet, can also be used in the management of hypercalcemia in recalcitrant HPT or as a bridge to definitive surgical therapy.
Vitamin D (25-hydroxy vitamin D) levels should be checked preoperatively and supplemented to reduce the risk of postoperative hypocalcemia. More severe postoperative hypocalcemia can occur in patients with preexisting bone disease or vitamin D deficiency, a condition known as the “hungry bone syndrome” and manifested by hypocalcemia, hypophosphatemia, and hypomagnesemia.57
PTH levels drop immediately after successful surgical resection, and calcium levels follow in the next 24 to 48 hours.58 Therefore, cure can be determined shortly after surgery. Despite normal calcium levels, PTH levels may remain elevated in a secondary fashion and should not be misinterpreted as recurrent or residual disease.59 In pediatric patients with primary HPT, there is up to a 6% rate of recurrence.46 This is more likely in patients with genetic syndromes of HPT, but recurrent adenomas can occur in sporadic cases. Thus, annual screening with calcium and PTH levels should be considered.
Parathyroid Carcinoma
Epidemiology and Pathophysiology
Parathyroid carcinoma (PTCa) is extremely rare, accounting for <1% of all cases of primary HPT; the incidence in children is unknown. PTCa occurs in all age groups and gender distribution is equal.60 Predisposing factors for the development of PTCa include a history of neck irradiation, prolonged secondary HPT, and end-stage renal disease on hemodialysis. Malignant transformation from a preexisting adenoma or hyperplasia does not appear to occur. Somatic and germline mutations in CDC73 (HRPT2) (Table 36.1) are also a risk factor for PTCa and important to consider in patients presenting with severe HPT.61
Clinical Presentation and Diagnosis
The clinical features of PTCa are due to severe hypercalcemia and tumor mass infiltrating vital organs. Malignancy is suggested with a severe clinical presentation, palpable neck mass, serum calcium levels >14 mg/dL, significantly elevated PTH levels, and elevated alkaline phosphatase.61,62 Pathologically, PTCa is difficult to distinguish from benign tumors. The diagnosis can be unequivocally made only in those tumors with documented metastases or in tumors that invade adjacent soft tissues, thyroid gland, blood vessels, and/or perineural spaces. Given the possibility of CDC73 mutations in PTCa, immunohistochemistry for parafibromin (the protein encoded by CDC73) may also assist in the pathologic diagnosis.61 Fine-needle aspiration is not recommended because of potential seeding of malignant cells and the inability to make an accurate histologic diagnosis.
Treatment
The recommended treatment for PTCa is an en bloc resection of the primary lesion together with the ipsilateral thyroid lobe and isthmus, central lymph nodes, thymic tongue, and any adherent tissue to the tumor, including the recurrent laryngeal nerve if needed.60,61 Extensive lateral neck dissection is not recommended unless there are grossly enlarged lymph nodes, and great care must be taken to avoid tumor spillage.
In appropriate cases, distant metastatic disease can be treated with surgical metastasectomy or targeted ablation. Systemic chemotherapy for PTCa is not well studied and has limited efficacy. Agents that have been used include combinations of dacarbazine, cyclophosphamide, 5-FU, vincristine, and doxorubicin.60,62 Radiation therapy may be considered in terms of locoregional control.62 The medical management of refractory symptomatic hypercalcemia includes intravenous bisphosphonates, subcutaneous salmon CTN, plicamycin (mithramycin), gallium nitrate, denosumab, and/or cinacalcet.60,63
Staging and Prognosis
Two systems for the prognostic risk classification of parathyroid cancer that are based on histologic findings have been proposed.61 In general, PTCa is a slow-growing yet progressive tumor that tends to recur locally or spread to contiguous structures in the neck. Metastases occur later in the course of the disease via lymphatic or hematogenous spread. Cervical lymph nodes, lung, and liver are the most common metastatic sites. Recurrence rates are high, and the average time between surgery and first recurrence is approximately 3 years, noting that prolonged disease-free intervals have been reported. Disease-specific mortality usually results from uncontrolled hypercalcemia, and a median overall survival of 14.3 years has been observed.64
THYROID TUMORS
Benign Thyroid Neoplasms
Epidemiology and Pathophysiology
In a child presenting with a thyroid nodule ≥1 cm in size, the likelihood of malignancy is approximately 22%,65,66 compared with a 5% to 15% rate of malignancy in adults.67 Functioning nodules (Fig. 36.4) associated with subclinical or overt hyperthyroidism represent a minority of thyroid nodules, and these “hot” or toxic thyroid neoplasms have been associated with somatic mutations in the TSH receptor (TSHR) or GNAS genes.32 Risk factors associated with developing thyroid nodules include iodine insufficiency, exposure to ionizing radiation, a family history of thyroid disease, and a personal history of autoimmune thyroid disease.68 In addition, there is an increased prevalence of benign and malignant thyroid nodules in certain genetic syndromes (Table 36.1).
Clinical Presentation and Diagnosis
Thyroid nodules are usually asymptomatic, although those children with functioning nodules may present with classic signs and symptoms of hyperthyroidism. Many nodules are identified during routine physical exam, but an increasing number are incidentally discovered during an unrelated radiologic exam. Pediatric thyroid nodules should be evaluated with thyroid function testing, thyroid and neck US, and fine-needle aspiration biopsy (FNAB). While the routine measurement of CTN remains controversial, measuring the thyroid-specific glycoprotein thyroglobulin (TG) is not recommended because elevated TG levels are identified in a variety of benign thyroid processes, thereby lowering the specificity of this diagnostic test.69
Thyroid US can provide information on size, location, echogenicity, blood flow, multiplicity, and potential involvement of regional lymph nodes by cancer (Fig. 36.5). US facilitates the accuracy of FNAB of both the primary thyroid lesion(s) and suspicious cervical lymphadenopathy, which greatly assists with surgical planning. Benign US characteristics include a hyperechoic, homogenous internal architecture of the nodule; complete cystic composition; the presence of a translucent halo; eggshell calcifications; and/or a smooth, well-defined margin. In contrast, findings suggestive of malignancy include a hypoechoic pattern, subcapsular localization, increased peri- and intranodular vascularization, the presence of microcalcifications, and/or irregular/jagged margins.70
Nuclear scintigraphy using 123I or 99mTc-pertechnetate is not indicated in the initial evaluation of a thyroid nodule, except in patients with a low TSH (Fig. 36.4) or in those with an FNAB diagnosis of follicular lesion or neoplasm, in whom nodule functionality may help to determine management.67
 Figure 36.4 Functioning or “hot” nodule. A: A large thyroid nodule involving most of the right thyroid lobe is clearly visible on physical examination. B: On 123I thyroid uptake and scan, only the toxic nodule is identified; the remainder of the normal thyroid tissue is appropriately suppressed. |
FNAB is the most efficient and accurate method of evaluating the etiology of a thyroid nodule in pediatric patients.66,67,71,72 Cytologic examination of the FNAB sample should be performed at the bedside in order to establish adequacy of the sample and to determine if additional samples are needed for an accurate diagnosis. In patients with multinodular disease, the selection of nodules to undergo FNAB should be based on US characteristics, not necessarily nodule size.67
Treatment and Follow-up
In most children with functional thyroid nodules, surgery is the preferred treatment, although 131I therapy can also be considered. For nonfunctional thyroid neoplasms, treatment and follow-up are determined by the cytopathologic diagnosis.67,73,74,75 For patients with malignant/suspicious cytology or a diagnosis of follicular neoplasm, surgery is recommended. In patients with nondiagnostic or indeterminate results, such as follicular lesion of undetermined significance, repeat FNAB or surgery is the most appropriate next step. Given the lack of established molecular or biochemical markers to accurately distinguish benign from malignant disease in children with an indeterminate biopsy, the decision to proceed to surgery is based on clinical criteria such as age of the patient, family history, nodule size, US criteria, history of radiation exposure, and others.66,76 In patients with benign
cytology, annual physical exam and US are appropriate, with repeat FNAB if the nodule grows significantly.75 TSH suppression with exogenous levothyroxine is no longer recommended in the euthyroid patient.66,67
cytology, annual physical exam and US are appropriate, with repeat FNAB if the nodule grows significantly.75 TSH suppression with exogenous levothyroxine is no longer recommended in the euthyroid patient.66,67
 Figure 36.5 US findings of benign and malignant thyroid neoplasms. A: Benign colloid nodule with mixed solid [S] and cystic [C] components. B: Multiple benign thyroid cysts [C] in a different patient. C: PTC diffusely involving the thyroid gland with characteristic scattered microcalcifications. D: Metastatic lymphadenopathy (yellow arrows) identified in the same patient as (C). |
Malignant Thyroid Neoplasms
Thyroid carcinoma is the most common endocrine malignancy, with an estimated 62,980 new cases diagnosed in the United States during 2014, of which only 1.8% occur in individuals <20 years of age.77,78 The incidence is ≤1 case/million/y in children under 10 years of age to 18 cases/million/y in adolescents ages 15 to 19, the most commonly affected pediatric age group.79,80
Thyroid malignancies arise from the thyroid follicular epithelium (differentiated thyroid carcinoma [DTC]: papillary thyroid carcinoma [PTC], follicular thyroid carcinoma [FTC], and their variants) or the neural crest-derived parafollicular C cell (medullary thyroid carcinoma, MTC).9 Anaplastic (undifferentiated) thyroid carcinomas and poorly DTCs are exceedingly rare in childhood, as are primary thyroid lymphomas and metastases to the thyroid gland. Several multidisciplinary guidelines have been created to assist with clinical decision-making in the care of adult patients,67,74,81 and specific guidelines for the evaluation and management of DTC in children are in development.
Differentiated Thyroid Carcinoma
Epidemiology and Pathophysiology
DTC is the most common thyroid malignancy, with PTC representing 90% or more of cases.80,82 PTC is typically a disease of young women, and the female:male incidence is greater than 5:1 in adolescents.79,83 This gender difference is not pronounced in children younger than 10 years. Subtypes of DTC include conventional, follicular, tall cell, columnar cell, diffuse sclerosing, solid and encapsulated variants in PTC; and Hürthle-cell (oncocytic), clear cell, and insular (poorly differentiated) carcinoma in FTC.9 In contrast to the classical type found in older individuals, childhood PTC, particularly in patients less than 10 years of age, may be unencapsulated, widely invasive throughout the gland, and have a follicular and solid architecture with unique nuclear features and abundant psammoma bodies.84
The major established environmental risk factor for the development of PTC is therapeutic radiation exposure to the head and neck. Children, particularly those <age 5, are much more sensitive to the tumorigenic effects of ionizing radiation,85 which may in part be due to the higher rate of thyroid cell replication in children as compared with adults. In the youngest children, radiation therapy not including the thyroid region can also increase the risk of PTC. The risk of malignancy paradoxically appears to decline once the thyroid dose exceeds 200 cGy,86 and radiation-induced PTC does not appear significantly different in clinical behavior compared with sporadic non-radiation-induced tumors.87 Interestingly, thyroid cancer in childhood cancer survivors is increased even in those children who did not receive therapeutic irradiation.88 Internal ionizing radiation, as seen with the large environmental exposure to radionuclides from the Chernobyl nuclear accident, is also associated with the development of PTC, particularly in children less than 10 years of age when exposed.82 The small doses of 123I/131I used in diagnostic studies and the treatment of hyperthyroidism appear to be below the threshold needed for tumorigenesis.89 Iodine insufficiency is associated with an increased incidence of FTC, and as with many other cancers, obesity may be an additional risk factor.90
Recent advances in the molecular and genetic basis of DTC have improved understanding of disease pathogenesis and provided new targets for therapeutic intervention. Activation of the mitogen-activated protein kinase signaling pathway is important in DTC tumorigenesis. One of the major early somatic events associated with the development of PTC is a chromosomal rearrangement linking the promoter region of an unrelated gene(s) (“PTC”) to the carboxyl terminus of the RET (REarranged during Transfection) proto-oncogene.91 The RET/PTC rearrangement produces a chimeric oncogene, resulting in a constitutively activated form of the RET receptor tyrosine kinase that is not normally expressed in thyroid follicular cells.
Mutations in BRAF are the most common cause of PTC in adults, occurring in 36% to 83% of cases.92 PTCs that are positive for a BRAF mutation are often interpreted pathologically as tall cell variants and are more clinically aggressive.93 Children and young adults are less likely to harbor somatic BRAF mutations, and RET/PTC rearrangements are more common in this population.82,94 Other genes and gene products involved in tumorigenesis include RAS (PTC and FTC); the TRK proto-oncogene (rearranged akin to RET, but found in a minority of PTCs); Pax8-P-PARγ1 translocations (follicular adenomas and follicular thyroid carcinomas only); MET overexpression (mostly in PTCs); the p53 tumor suppressor gene (specifically involved in anaplastic thyroid cancer); PIK3CA (mostly FTC); and the AKAP9-BRAF gene fusion (radiation-induced PTC carcinomas developing after a short latency period).91,92,95
Up to 5% of patients with PTC have a family history of the disease.96 Having familial nonmedullary thyroid carcinoma (FNMTC) may portend a worse prognosis and require more aggressive treatment.97 The genetic basis for FNMTC has not yet been elucidated. Other familial tumor syndromes in which there is an increased risk of DTC include APC-associated polyposis, CNC, PTEN hamartoma tumor syndrome, and Werner syndrome, and CNC5 (Table 36.1).
Clinical Presentation and Diagnosis
DTC usually presents as an asymptomatic neck mass, although occasionally the diagnosis is made after the discovery of distant metastases (Fig. 36.6). DTC can uncommonly arise ectopically in a thyroglossal duct remnant or cyst or be identified incidentally after surgery for benign thyroid disease. Locally metastatic disease is present at diagnosis in the vast majority of pediatric PTC cases. In addition, compared with adults, children more often have disseminated disease at diagnosis, with the lungs being the primary site of distant disease. Metastases to other sites such as bone and brain are rare.
PTC and FTC have key differences in clinical behavior, likely due to different underlying mutational events. PTC is more likely to metastasize via lymphatic channels to regional neck lymph nodes, with hematogenous metastases, primarily to the lung, occurring less often and typically only when significant locoregional lymph node metastases are present.98,99 FTC, on the other hand, is more prone initially to hematogenous metastases (affecting predominantly the lungs and bones). Metastasis to regional lymph nodes is uncommon, but can be seen with some of the less-differentiated FTC subtypes. Furthermore, PTC is more likely to be multifocal and bilateral; FTC, in contrast, is usually a unifocal tumor.
A high-quality neck US and FNAB of suspicious lymph nodes are critical in the initial evaluation of DTC76 (Fig. 36.5). Nuclear imaging studies are not helpful in the initial evaluation of thyroid cancer patients, and thyroid function studies are anticipated to be normal in most cases. DTC cells retain the ability to produce TG, and once the diagnosis of DTC is established, a baseline TG will be useful for follow-up and for the potential identification of a large metastatic disease burden. TG autoantibodies should always be measured concomitantly, as these occur in up to 25% of thyroid cancer patients and render the TG level uninterpretable.100 A chest x-ray or chest CT to assess for pulmonary metastases can be considered at diagnosis, especially in those patients with significant locoregional disease, noting that many individuals with lung metastases may not have abnormalities visualized on plain radiographs.101 Finally, cross-sectional imaging of the neck (CT with contrast or MRI, depending upon local expertise) is recommended
for patients with significant metastatic neck lymphadenopathy, as the superior mediastinum and central compartment are not well visualized via US. Although the use of iodinated contrast will briefly delay subsequent 131I therapy,102 the information gained should allow for better surgical planning and oncologic outcomes.
for patients with significant metastatic neck lymphadenopathy, as the superior mediastinum and central compartment are not well visualized via US. Although the use of iodinated contrast will briefly delay subsequent 131I therapy,102 the information gained should allow for better surgical planning and oncologic outcomes.
 Figure 36.6 Clinical presentations of pediatric PTC. A: Large infiltrating thyroid mass (blue arrows) with bilateral palpable metastatic lymphadenopathy (yellow arrowheads). B: MRI of the same patient in (A) demonstrating bulky metastatic lymphadenopathy (yellow arrowheads) and an incidental brain metastasis (red arrowhead). C: Lung metastases typically appear as multiple well-defined pulmonary nodules that are more prominent in the lung bases. |
Staging and Prognosis
Although several prognostic staging systems have been described for thyroid cancer, specifically PTC, a thorough discussion of these is beyond the scope of the current chapter. The pathologic tumor-node-metastasis (TNM) classification was adopted by the American Joint Committee on Cancer and the International Union against Cancer Committee (UICC) as the international reference staging system for thyroid cancer.103 By definition, however, the highest TNM stage that anyone less than age 45 can achieve is stage II, distinguished from stage I only by the presence of distant metastases. Another frequently used staging system, the MACIS score, may also be useful in children and adolescents but requires further validation.104
Most children with DTC having an excellent prognosis and survival over decades is generally the norm for these patients, even in the presence of distant metastases at diagnosis. Remission rates are high, and 10-year survival is almost universally 100% in this age group.80,83,105,106 For patients with stage II disease, those with micronodular lung metastases and iodine-avid disease (i.e., disease that retains good expression of the sodium-iodide symporter) have the best prognosis.107 Some children with DTC will ultimately succumb to their disease or die from treatment-related complications.105,106,108 Children diagnosed prior to age 10 appear to have a higher risk of recurrence and ultimately death from their disease,84,109,110 although this has not been observed universally.111 It remains unknown why children with a similar extent of disease presentation have a much better prognosis compared with adults, but it is suspected that underlying mutational differences play a role, in addition to the knowledge that pediatric thyroid cancer tends to be more iodine-avid and responsive to TSH suppressive therapy.
Treatment and Follow-up
Surgery. Surgery is the cornerstone of therapy for DTC and total thyroidectomy is the initial procedure of choice, since it has been associated with lower recurrence rates and better survival compared with lobectomy alone, particularly for tumors greater than 1 cm in size.105,112,113 In addition, total thyroidectomy facilitates 131I therapy, if indicated. All lymph node dissections should be comprehensive and compartment focused because the rates of recurrence are higher when “berry picking” alone is undertaken.114 Although total thyroidectomy and central compartment lymph
node dissections are associated with higher risks, such as permanent hypoparathyroidism and recurrent laryngeal nerve injury, these risks should be minimized when the surgery is performed by a high-volume surgeon.52,53
node dissections are associated with higher risks, such as permanent hypoparathyroidism and recurrent laryngeal nerve injury, these risks should be minimized when the surgery is performed by a high-volume surgeon.52,53
The diagnosis of FTC is established only after the pathologic identification of capsular and/or vascular invasion of a resected “follicular lesion” or “follicular neoplasm.” For patients with a solitary nodule and a minimally invasive FTC, lobectomy alone may suffice.67,115 Total thyroidectomy should be considered if there are bilateral nodules and/or there is significant vascular invasion. In addition, total thyroidectomy facilitates postoperative staging to determine if there are distant metastases that would benefit from 131I treatment. The lymph nodes should be managed similar to PTC in poorly differentiated tumors and more aggressive variants such as Hürthle cell carcinoma.
Radioactive Iodine/External-Beam Radiation Therapy. In previous decades, the majority of patients with DTC were administered 131I to ablate normal remnant thyroid tissue, thus improving the sensitivity to identify residual or recurrent disease via nuclear scintigraphy and serial TG measurements. Data from prior studies reported that 131I lowered recurrence rates and cancer-related mortality in patients whose tumors concentrate iodine.116,117 However, recent studies in adults have demonstrated that low-risk patients may not clearly benefit from adjuvant 131I.67,118 This issue has not been prospectively studied in pediatric DTC, and the possible benefits of 131I must be weighed against the potential risks of therapy.
Following thyroidectomy, the child with DTC is usually rendered hypothyroid via thyroid hormone withdrawal with plans to administer 131I when the TSH is >30 µU/mL.76 Recombinant human TSH (rhTSH) can also be utilized in low-risk patients, and its use may result in a lower absorbed dose to the blood compared with 131I treatment after withdrawal.119 However, prospective studies in children using rhTSH are lacking. A low-iodine diet is generally advised for 2 weeks to facilitate uptake by any remaining thyroid tissue. Most centers routinely obtain a pretherapy (or diagnostic) whole-body scan using 131I or 123I (preferred) to screen for persistent cervical disease, to assess for distant metastases, and to determine whether a patient may benefit from 131I.76,120,121 In addition to the results from the diagnostic scan, the decision on whether to administer 131I is based on histopathologic features/TNM staging and, in the absence of anti-TG antibodies, the stimulated TG. There are no standardized recommendations for the use of therapeutic 131I in children, and the dose is generally based on a weight (or Body Surface Area (BSA)) adjustment of the typical adult dose used for a similar extent of disease. Dosimetric studies to limit whole-body retention at 48 hours to less than 80 mCi and blood/bone marrow exposure to less than 200 cGy should be considered in those children anticipated to have significant diffuse lung uptake with 131I therapy and those children with more widespread distant metastases.122 A posttreatment thyroid scan, sometimes coupled with SPECT imaging123(Fig. 36.7), should be obtained 5 to 8 days after the administration of 131I to identify other sites of persistent disease that were not apparent on the diagnostic study.101,122
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