Although pituitary and sellar region tumors are relatively rare in infancy and childhood (overall incidence rate of approximately 0.5 per 100,000 person years), these tumors still account for up to 12% of all childhood primary brain and CNS tumors and between 2% and 10% of transsphenoidal procedures. To provide optimal care, it is important to characterize the unique epidemiology, presentation, and management of these tumors in this patient population. Particular challenges in the pediatric population include understanding how the endocrinological perturbations associated with pituitary tumors uniquely affect the developing body and account for the incompletely aerated sinuses of children, which can complicate the transsphenoidal approach.
The vast majority of sellar region tumors in those less than 20 years of age are functioning pituitary adenomas (especially ACTH and prolactin-secreting adenomas), Rathke cleft cysts, and craniopharyngiomas in contrast to adults in whom nonfunctioning adenomas predominate. Estimates of the proportion of pediatric brain and CNS tumors that are pituitary or sellar region tumors vary across studies, largely dependent on the age of inclusion. This likely reflects the increasing incidence of these tumors in adolescents. According to the Central Brain Tumor Registry of the United States (CBTRUS), whereas pituitary adenoma and craniopharyngioma account for 7.5% of all brain tumors in children up to 14 years old, they account for approximately 22% in adolescents aged 15 to 19 years. While craniopharyngiomas occur in equal numbers in boys and girls (0.15 cases per 100,000 person years), pituitary adenomas occur more frequently in girls than boys (up to three times as frequently).
The type of functioning pituitary adenoma varies as a function of age. ACTH-secreting adenomas are most commonly seen in prepubescent children (up to 11 years), with a diminishing incidence in older (pubescent and postpubescent) children. In contrast, prolactinoma incidence increases significantly with age. The incidence of GH- secreting adenomas remains relatively constant throughout childhood and adolescence. Craniopharyngiomas, on the other hand, peak in the 5-to-9-year-old age group in the pediatric population, with a peak incidence of 0.19 per 100,000 person years.
Clinical Signs and Presentation
While children, like adults, can have symptoms of either endocrinopathy or mass effect, sellar region tumors in children most often manifest with symptoms of endocrine dysfunction because of a combination of both hormonal hypersecretion and hypopituitarism. This presentation pattern likely reflects the disproportionate number of functioning pituitary adenomas (relative to nonfunctioning adenomas) seen in this patient population. Moreover, the signs and symptoms attributable to endocrine dysfunction are often more pronounced and dramatic in children than in adults because of the critical role that the pituitary gland plays in the normal growth (e.g., height) and sexual maturation. Hypopituitarism results both from tumor mass effect as well as feedback inhibition of the gland from hypersecretion of other hormones. The first and most commonly affected hormonal axis is that of growth hormone, accounting for the large number of patients having short stature. Gonadotropin dysregulation usually ensues, resulting in amenorrhea and either delayed sexual maturation or precocious puberty. Finally the thyroid hormone and adrenal axes can be disrupted.
In addition to the signs and symptoms attributable to hypopituitarism, functioning adenomas produce unique hypersecretion syndromes in the developing patient. In those with ACTH-secreting adenomas, the most common and consistently reported symptom is weight gain, which in distinction to adults is in a generalized distribution rather than a centripetal pattern. Growth delay is also a relatively consistent presenting symptom, due to both a direct effect of hypercortisolemia on impaired bone metabolism (resulting in decreased bone density) and an indirect effect of growth hormone deficiency from hypopituitarism. Other common signs and symptoms include moon facies, acne, hirsutism, hypertension, growth delay, amenorrhea, precocious puberty, fatigue, and headache.
In those with prolactin-secreting adenomas, signs and symptoms attributable to hormonal hypersecretion include primary (or secondary) amenorrhea, galactorrhea, gynecomastia, and hypogonadism (in males). The clinical manifestations of growth hormone-secreting adenomas depend on the developmental stage of the child. In prepubescent children, growth hormone hypersecretion results in gigantism, typified by tall stature, enlarged hands and feet, thickened skin, and prognathism. In postpubescent patients, growth hormone hypersecretion produces the typical stigmata of acromegaly seen in adults, including enlargement of the hands and feet, overgrowth of the skull and facial bones, macroglossia, sleep apnea, hypertension, glucose intolerance, arthritis, carpal tunnel syndrome, hyperhidrosis, and systemic cardiovascular disease.
Although rare, clinically nonfunctioning tumors can also occur in the pediatric population, having symptoms of mass effect, manifesting as headache, visual field defect, and hypopituitarism (including growth and pubertal delay and primary amenorrhea) ( Figure 25-1 ). This highlights the contribution of mass effect on the endocrinopathic presentation of pediatric patients with pituitary tumors. Functioning adenomas are not uncommonly macroadenomas, although macroadenomas are rarely seen in the setting of Cushing’s disease.
Patients with craniopharyngiomas often have a triad of symptoms, including visual failure (due to compression of the optic apparatus), hormonal disturbance (e.g., short stature), and hydrocephalus (see Figure 25-1 ). The extent of hormonal disturbance can vary from panhypopituitarism to deficits of a single hormone of the anterior gland. Patients may also variably have diabetes insipidus.
Finally, in a small fraction of patients, pituitary lesions may be discovered incidentally while imaging the brain for other reasons. In many cases, these patients may be asymptomatic, constituting a pituitary “incidentaloma.” In these cases, treatment must be deferred until a full history, physical, and endocrinological evaluation is completed (described later). If patients are clinically and endocrinologically normal, these adenomas are considered “incidentalomas”; no active treatment is warranted and patients should be followed with interval scans. In those with consistent clinical signs or with laboratory abnormalities, therapy (medical or surgical) should be considered.
All patients with sellar region tumors must have a complete neurological, ophthalmological, endocrinological, and radiological workup. Neurological and ophthalmological examination should focus on signs and symptoms attributable to local mass effect from a pituitary tumor, including palsies of the cranial nerves of the cavernous sinus (III, IV, V, and VI) and compression syndromes of the optic apparatus (including a dilated fundoscopic examination to assess for optic nerve atrophy and visual field testing to evaluate for bitemporal hemianopsia).
Endocrinological workup must evaluate each facet of the hypothalamic-pituitary-end organ axis, not only to confirm the hypersecretory state and to evaluate for hypopituitarism, but also to identify the two important clinical scenarios in which primary surgical intervention is contraindicated: prolactinomas and pseudotumor due to primary hypothyroidism. Unlike in the adult patient, serial growth charts are an essential part of the endocrine evaluation and often provide clues not only to the disease onset but response to treatment.
Serum prolactin levels must be assayed and scrutinized in each patient. In general, prolactinomas will produce serum prolactin levels that are proportional to their size such that small adenomas will produce mild elevations in serum prolactin, whereas macroprolactinomas will produce much greater increases in serum levels (e.g., >200 µg/L). Mild prolactin levels may be due to either a small microadenoma or due to “stalk effect” of a larger nonprolactin- secreting functioning or nonfunctioning adenoma. In cases of high suspicion of prolactinoma, serial sample dilutions should be requested to avoid artificially low values due to the “hook effect.” It is imperative to differentiate between stalk effect, hook effect, and prolactin levels consistent with a prolactinoma since the first-line therapy for prolactinomas, even in children, remains medical.
The thyroid axis is evaluated by assaying both free thyroxine (FT 4 ) and thyroid-stimulating hormone (TSH) levels. A high TSH and FT 4 is consistent with a TSH-secreting adenoma, which is exceedingly rare in the pediatric population. On the other hand, an abnormally high TSH in the setting of a low or normal FT 4 may signify primary thyroid insufficiency resulting in pituitary hypertrophy (mimicking a tumor) due to lack of feedback inhibition from the thyroid hormone. The therapy for primary thyroid insufficiency is thyroid hormone therapy, which can normalize the size of the pituitary gland; surgical intervention is contraindicated. Finally, low TSH in combination with low FT 4 is consistent with secondary hypothyroidism due to pituitary insufficiency, which likely warrants hormone replacement therapy (with a thyroid hormone) but does not obviate the need for surgical intervention.
The adrenal axis must be evaluated either for insufficiency or hypercortisolemia, depending on the clinical scenario. Hypercortisolemia is best confirmed with 24-hour urinary free cortisol measurements (age permitting). Alternative tests to confirm hypercortisolemia are performed to demonstrate failure to suppress morning serum cortisol levels with overnight low-dose dexamethasone administration. The vast majority (~85%) of hypercortisolemia in children is due to a central cause. Nonetheless, radiographic or laboratory investigation into the precise cause in each patient is warranted. A high-dose dexamethasone suppression test can be used. Recently, many have come to rely on inferior petrosal sinus sampling (IPSS) rather than high-dose dexamethasone suppression tests, even when there are positive MRI findings. In addition to confirming pituitary etiology, IPSS has been reported to be more accurate for lateralizing the tumor than imaging (91% vs. 9% accuracy). With modern imaging and pulse sequences, what used to be negative or ambiguous findings on MRI have become clearer, decreasing the demand for IPSS on all patients. Our practice is to obtain IPSS only if the MRI remains ambiguous. Adrenal insufficiency is best evaluated by measuring a morning serum cortisol measurement (when cortisol values are expected to be highest). Chronic hypocortisolemia can also affect bone metabolism and bone density, sometimes warranting bone density scans to assess the degree of bone demineralization.
To evaluate growth hormone status, serum GH and insulin-like growth factor (IGF-1) levels are measured. In case of suspected growth-hormone secreting tumors, an oral glucose tolerance test (i.e., provocative testing) can be used. The oral glucose tolerance test is best employed in follow-up to confirm remission. Radiographs can also be obtained to assess bone age relative to chronological age.
Serum gonadotropins should also be assayed in all patients and may provide insight into mechanisms of delayed sexual maturation and amenorrhea. Posterior gland dysfunction, manifested as diabetes insipidus, is investigated by obtaining a detailed history of polydipsia, polyuria, and nocturia. Serum electrolytes and urinalysis should also be evaluated, although may not be abnormal in the setting of intact thirst mechanisms and access to fluids.
Although most reported large series of pediatric pituitary tumors encompass the pre-MRI era, modern management of pediatric sellar-region tumors required dedicated MR imaging of the sella. With modern imaging and pulse sequences, what used to be negative or ambiguous findings on MRI have become clearer, increasing its relative importance in steering treatment. Still, it is not unusual to fail to identify an adenoma in the setting of Cushing’s disease, requiring adjunctive diagnostic modalities (as described previously) to localize the tumor.
One of the particular challenges of transsphenoidal surgery in the pediatric population is the pneumatization of the sphenoid sinus ( Figure 25-2 ). At times, a computed tomography (CT) scan may therefore be useful to assess the degree of sinus aeration for appropriate surgical planning. Moreover, CT-guided neuronavigation may provide an advantage when landmarks normally seen in adult patients may not be clear.