Chapter 3 – Pituitary adenomas in childhood

Updated 2 December 2010

Introduction

The pituitary function depends on the integrity of the hypothalamo-pituitary axis and the functionality of numerous differentiated cell lines in the anterior pituitary lobe that specialize in specific hormone production. The development of these cell lines is the result of events during pituitary organogenesis that are under the sequential control of transcription factors (1). Any abnormality occurring in the pituitary gland either congenital (congenital malformations, genetic abnormalities) or acquired (perinatal insults, tumors, infections) will cause profound alterations of the whole endocrine system.
Tumors in the pituitary region can be classified on the basis of topographic criteria as intra-, supra- para- or retrosellar. Intrasellar tumors are mostly represented by pituitary adenomas (more than 90% of all intrasellar lesions), while dysembryogenetic lesions such as Rathke's pouch cyst are less frequent. The suprasellar tumors are dysembryogenetic lesions of the midline such as craniopharyngiomas, germinomas, dermoid or epidermoid cysts, lipomas, teratomas, hamartomas. Other tumors such as meningiomas or gliomas are uncommon during childhood or adolescence. Craniopharyngiomas, the most common cause of hypopituitarism in childhood, and adenomas are the most frequent lesions of the pituitary region in children and adolescents. Virtually all tumors of this region are benign.
This chapter aims at reviewing the most recent epidemiological, diagnostic and therapeutic knowledge on pituitary tumors in childhood and adolescence.

Craniopharyngiomas

Craniopharyngiomas account for 80-90% of neoplasms arising in the pituitary region. They originate from squamous rest cells of the remnant of Rathke's pouch between the adenohypophysis and neurohypophysis in the region of the pars tuberalis. Rathke's pouch is a cystic diverticulum from the roof of the embryonic mouth that gives rise to the adenohypophysis and determines the induction of the neurohypophysis. This tumor constitutes 3-5% of all intracranial expanding lesions (2), 6% during the pediatric age (3), and shows a bimodal distribution during the first-second decade of life and then in the fifth (4), apparently without any gender difference (5). The tumor generally originates in the suprasellar region (90%), whereas intra- and suprasellar localizations (18%) or solely intrasellar (5%) are less frequent, and extremely rare the forms originating in the III ventricle (2), in the rhinopharynx or in the sphenoid (6,7). The overall incidence of craniopharyngiomas in the United States is 1.3 /10-6 person/ year (8).
Craniopharyngiomas are benign from a histological evaluation but they can be aggressive, invading surrounding bony structures and tissues; they commonly have cystic components that may be multiple and generally cause compression of adjacent neurological structures.

Clinical presentation and diagnosis

The diagnosis of craniopharyngioma is often made late, sometimes years after the initial appearance of symptoms. Neurological disturbances, such as headache and visual field defects, together with manifestations of endocrine deficiency such as stunted growth and delayed puberty are the common presenting symptoms of craniopharyngiomas. Stretching of the diaphragm sellae by the enlarging mass is one of the most likely cause of headache, while obstruction of the aqueduct of Sylvius or the foramina of Monro is a rare complication (8). At diagnosis, endocrine dysfunctions are found in up to 80% of patients (9). Reduced GH secretion is the most frequent finding, present in up to 75% of patients, followed by FSH/LH deficiency in 40%, ACTH and TSH deficiency in 25%. Despite the fact that the tumor is frequently large at presentation, the pituitary stalk is usually not disrupted, and hyperprolactinemia secondary to pituitary stalk compression is found in only 20% of patients. Diabetes insipidus is also relatively uncommon, occurring in 8-35% of patients (10,11). The recent availability of high resolution magnetic resonance imaging (MRI) has greatly improved the visualization and radiological diagnosis of craniopharyngiomas. The results of previously published series based on plain skull x-rays have now to be revised. The neuroradiological diagnosis of craniopharyngiomas is based on the features of the lesion itself and on its relations with the surrounding structures. The diagnosis is mainly based on the three characteristic components of the tumor: cystic, solid and calcified (12,13). The cystic component (Fig.1) constitutes the most important tumor part (up to the 70-75% of the total volume), and shows a variable signal depending on the chemical-physical properties of its content (14). A fluid content will appear hypointense in T1 and hyperintense in T2 while a lipid (due to cholesterol), methemoglobin or protein content will appear as hyperintense in T1 and T2 sequences. The solid portion shows an isointense signal in T1 and a hyperintense signal in T2 with an enhancement after gadolinium, at variance with the cystic component (Fig.2). However, the enhancement after paramagnetic contrast is not a consistent feature (14). Calcifications appear as areas of low signal in all sequences; small calcifications can be better visualized at computed tomography (2). The radiological appearance of non-homogeneous signal at prevalent cystic component should not be regarded as a proof of a craniopharyngioma, since macroadenomas can also be characterized by patterns resembling craniopharyngiomas (Fig.3,4).

Treatment strategy

The clinical presentation of patients may be as an emergency with symptoms of raised intracranial pressure or rapid deterioration in visual function. Initial surgical treatment, for hydrocefalus or tumor cyst decompression, to relieve these symptom and prevent further visual deterioration may be necessary, prior to definitive treatment of the tumor (15). The treatment of choice is total tumor resection. The operative approach is generally dictated by localization and extent of the craniopharyngioma. A right frontotemporal approach is standard, but intrasellar tumors can be operated on by the trans-sphenoidal route. Craniopharyngioma arising in childhood usually extend to the suprasellar area and must be removed through a transcranial approach (16). In small intrasellar or enclosed tumors, total resection is most easily achieved, and adjunctive radiotherapy is unnecessary. Radiotherapy is required in case of incomplete tumor removal which is common for extra-sellar craniopharyngiomas (the majority of cases). Surgical morbidity depends on tumor size and invasiveness, the experience of the surgeon, and the route of surgical approach. The risk of hypothalamic damage is significantly greater in large invasive tumors treated by trans-cranial approach. Near total excision of the tumor by an experienced pituitary surgeon sparing the hypothalamus, carotids, and visual apparatus, followed by fractionated radiotherapy provides the best hope of low long-term morbidity and longer survival (16-19). Regardless of the approach, the incidence of endocrine dysfunction is high following surgical treatment (17,20), although it is lower after the trans-sphenoidal approach (16). Post-operative diabetes insipidus is reported in 70-90% after surgery (11). Obesity is also frequently found postoperatively: 25 of 43 children with craniopharyngioma became obese after surgery particularly if BMI SDS at presentation was higher and hydrocephalus was present pre-operatively (21). Observations indicate that reduced physical activity and increased daytime sleepiness might also be risk factors for obesity (22).
Localized intracavity Yttrium, 32P, and other radioactive implants, given as additional treatment, have proven useful for recurrent tumors with a predominant cystic component (8). Hyperfractionated multiportal stereotactic radiotherapy and γ-knife radiosurgery are promising therapeutic alternatives to standard radiotherapy, due to their potential ability to reduce treatment-associated morbidity in this condition. In children, however, the benefit of any additional radiotherapic treatment should be balanced against the high risk of inducing hypopituitarism later in life. In a retrospective preliminary review aiming at evaluating the efficacy and toxicity of fractionated proton radiotherapy in the management of pediatric craniopharyngioma local mass control was reported in 14 of 15 patients with few acute side effects and newly diagnosed panhypopituitarism, cerebrovascular accident (from which the patient recovered), and an out-of-proton-field meningioma in a single patient who received previous radiotherapy as long-term complications (23).
However, attention should be paid toward late effects arising after treatment of pediatric craniopharyngioma, including decreased postoperative physical health and behavioral functioning (24).

Pituitary adenomas

Pituitary adenomas are the most common cause of pituitary disease in adults but they are less common in children, becoming increasingly more frequent during adolescent years (25-27). The estimated incidence of pituitary adenomas in childhood is still unknown since most published series included patients with onset of symptoms before the age of 20 yrs as pediatric patients (28). Pituitary adenomas constitute less than 3% of supra-tentorial tumors in children, and 2.3-6% of all pituitary tumors treated surgically (28-31). The average annual incidence of pituitary adenomas in childhood has been estimated to be 0.1/million children (32). Among all supra-tentorial tumors treated during a 25-year period, pituitary adenomas were diagnosed in only 1.2% of children (33). Pituitary carcinomas are rare in adults and extremely rare in children (34).
There is no consensus on the alleged greater invasiveness of pituitary adenomas in children than in adults, while a slightly greater prevalence in females has been reported (8,26,32). However, gender distribution reflects the relative contribution of the two main groups, PRL- and ACTH-secreting adenomas, which predominate in most series reported. Prolactinoma is indeed the most frequent adenoma histotype in children, followed by the corticotropinoma and the somatotropinoma. Nonfunctioning pituitary adenomas, TSH-secreting, and gonadotropin-secreting adenomas are very rare in children accounting for only 3-6% of all pituitary tumors (28). ACTH-secreting adenomas have an earlier onset and predominate in the pre-pubertal period while GH-secreting adenomas are very rare before puberty(8,28).Similarly to adults, presenting symptoms are generally related to the endocrine dysfunction, such as growth delay and primary amenorrhea, rather than to mass effect (33-39).
Symptoms of pituitary tumor presentation differ according with the histotype as shown in Table 1 and detailed in the specific sections.

Table 1. Prevalence of clinical symptoms and signs in children/adolescents with pituitary adenomas. Data drawn from ref.33-39
	PRL-secreting adenomas	ACTH-secreting adenomas	GH-secreting adenomas	TSH-secreting adenomas	Clinically Nonfunctioning adenomas
Acne	-	+	-	-	-
Delayed/arrest growth	-/+	+	-	++	++
Delayed/Advanced bone age	-	+	+	-/+	++
Delayed puberty	++	+	+	+	++
Early sexual development	-	++	-	-	-
Erytrosis	-	+	-	-	-
Fatigue or weakness	-	+	-	+	-
Galactorrhea	+++	-	-/+	-	-
Gigantism/Acromegaly	-	-	++	-	-
Glucose intolerance	-	+	+	+	-
Gynecomastia	+	-	-/+	-	-
Headache	++	+	++	+	++
High school performance	-	+	-	-	-
Hirsutism	-	+	-	-	-
Hypertension	-	+	-/+	-/+	-
Menstrual irregularities	++	+	++	+	++
Mild hyperthyroidism	-	-	-	+	-
Osteoporosis	+	+	-	+	-
Premature telarche	++	-/+	-	-	-
Primary amenorrhea	++	+	++	+	++
Secondary hypopituitarism	+++	+++	+++	+++	+++
Sleep disturbances	-	+	-	++	-
Striae	-	+	-	-	-
Visual field defects	+++	--/+	+++	+++	+++
Weight increase	+	+	-	-	-
-= Absent; -/+ rare; --/+= very rare; +=present; ++=frequent; +++= frequent in macroadenomas.

PRL-secreting adenomas

Prolactinomas are the most frequent pituitary tumors both in childhood and in adulthood, and their frequency varies with age and sex, occurring most frequently in females between 20-50 years (25,40,41,42).

Clinical presentation and diagnosis

PRL-secreting adenomas are usually diagnosed at the time of puberty or in the post-pubertal period (24,26,41), and clinical manifestations vary in keeping with the age and sex of the child. Pre-pubertal children generally present with a combination of headache, visual disturbances, growth failure, and amenorrhea (Table 1). Growth failure is not, however, a common symptom: in fact in two different retrospective studies, 4% of 25 patients (42) and 10% of 20 patients (43) were reported to have short stature at the diagnosis of prolactinoma. Weight gain has been reported to occur in patients with hyperprolactinemia (44-46) but never described in children.
In a re-evaluation of the young/adolescent patients with hyperprolactinemia admitted to the University Federico II from January 1st 1995 to December 31st 2004 (47,48), short stature was found in 7 of 50 patients (14%), five girls and two boys, and another two patients, one girl and one boy, had their height below or at the 5° percentile and another 8 (3 girls) had their height between the 5° and 10° percentile. The height percentiles in the patients with extrasellar/invasive macroprolactinomas were lower than in those bearing smaller tumors (Fig.5). Additionally, all girls present with oligomenorrhea or amenorrhea, most also had galactorrhea; gynecomastia was present in 12 of 21 boys (57.1%) The most common symptoms of prolactinomas in peripubertal age are those associated with deficiency of the pituitary-gonadal axis. Menstrual irregularities in girls are common in all types of pituitary adenomas, except those causing Nelson's syndrome (35). Galactorrhea should be carefully investigated by expressing the breast, because teenagers may not spontaneously refer it as a symptom, and frequently it is not spontaneous. Headache and visual field defects predominate in patients bearing large adenomas (Table 2).

Table 2. Table 2: Presentation of prolactinomas in children and adolescents: the two-decade experience of the Department of Endocrinology and Oncology, University "Federico II" of Naples. Data drawn from reference 47.
	Microadenomas	Enclosed Macroadenomas	Extrasellar and/or Invasive Macroadenomas
No.	20	21	9
Girls/Boys	15/5	11/10	3/6
Age at diagnosis (yrs)	14.4-0.5	14.8-0.4	13.8-1.1
Basal PRL levels (μg/L)	138.4-21.6	671.4-161.9	2123-279
Tumor volume on MRI (mm3)	113.0-15.1	1145-145	2826-330
Symptoms (%)
Secondary or Primary Amenorrhea1	53.3%	72.7%	66.7%
Oligomenorrhea1	46.7%	18.2%	0%
Gynecomastia2	100%	60%	33.3%
Galactorrhea	42.8%	60%	33.3%
Visual field defects	0%	50%	66.7%
Headache	33.2%	80%	66.7%
1= Calculated only in girls; 2=Calculated only in boys.

Impairment of other pituitary hormone secretion was reported to occur in a minority of patients at diagnosis (35, 42,43) and in some patients hypopituitarism developed after surgery. In a more recent analysis (47), we can confirm that only the minority of patients bearing large adenomas had severe degree of hypopituitarism while a very few patients with either microadenomas or enclosed macroadenomas had isolated hormone deficiency (Fig.6). Macroadenomas at presentation are more likely in boys than in girls (27,30,42,43). In our series (47), microprolactinoma and enclosed macroadenomas were more frequent in females with a ratio of 1.7:1 while large macroprolactinomas were 2 times more frequent in males (Table 2).

Hyperprolactinemic patients have a decrease of the bone mineral density (BMD), and progressive bone loss has been demonstrated in untreated patients (49,50). Young hyperprolactinemic men were shown to have a more severe impairment of BMD than patients in whom hyperprolactinemia occurred at an older age (51). In 20 patients with diagnosis of hyperprolactinemia during adolescence, we found (52) significantly lower BMD values in adolescents than in young adult patients with hyperprolactinemia. This finding is confirmed in a large cohort of patients (47). In 22 patients all having a diagnosis of prolactinomas before the age of 18 yrs, the bone mineral density (BMD) at lumbar spine was significantly lower than in age-matched controls (Fig.7).

The use of drugs to increase bone mass, such as amino-bisphosponates has not been investigated.
The diagnosis of prolactinoma is based on the measurement of serum PRL levels and neuroradiological imaging. The differential diagnosis of hyperprolactinemia should consider any process interfering with dopamine (DA) synthesis, its transport to the pituitary gland or its action at lactotroph DA-receptors. A single measurement of PRL levels is unreliable since PRL secretion is markedly influenced by physical and emotional stress. Basal PRL levels greater than 200ng/l are diagnostic, whereas levels between 100 and 200ng/ml and the presence of a mass requires additional investigation to rule out mass effect versus a prolactinoma. Some peculiar conditions should, however, be reminded (53). Serial serum PRL measurements at 0, 30 and 60 min after the needle was inserted into an antecubital vein is a valuable and simple measure to identify stress-related hyperprolactinemia in order to avoid diagnostic pitfalls and unnecessary treatments. It is important to exclude from the assay the monomeric PRL forms, big-prolactin (b-PRL) and big big-prolactin (bb-PRL); the latter may contain immunoglobulin (IgG) (54). These molecular complexes are seldom active but may recorded by the PRL assay. The absence of a clinical syndrome of hyperprolactinemia will suggest the presence of macroprolactin. The "high-dose hook effect" could be a serious problem in the differential diagnosis between prolactinomas and nonfunctioning adenomas (NFPA): it is mandatory, in these cases and in every patient with pituitary mass and hyperprolactinemia, to dilute PRL samples routinely (1:10 and 1:100 dilutions) or to use alterative methods to immunoradiometric assays. The difference between macroprolactinomas and "pseudoprolactinomas" is essential to provide a correct treatment approach (55). This problem is, however, of little value in children and adolescents as non functioning macroadenomas are very rare at this age.

Treatment strategy

Indication for therapy are: 1) to reduce tumor size, 2) to control PRL excess. In the absence of complications needing immediate surgery, such as visual loss, hydrocephalus, or cerebrospinal fluid leak, pharmacotherapy with dopamine-agonists (e.g. bromocriptine, pergolide, or cabergoline) should be considered the first treatment approach (25,47,48). Treatment with dopamine-agonists is effective in normalizing PRL levels and shrinking tumor mass in the majority of adult patients with prolactinoma (25,47). In children and adolescents, bromocriptine (BRC) has been used successfully by several investigators (42,56-59). In our series, BRC at doses ranging from 2.5-20 mg/day orally, induced normoprolactinemia in 38.5% of patients (42). In the remaining patients, 10 with macro (Fig.8) and 6 with microprolactinoma (Fig.9), PRL levels remained above the normal range despite a progressive increase of the dose of the drug. However, the possibility that some patients were indeed not taken BRC appropriately cannot be ruled out as poor compliance to any chronic treatment is a well known phenomenon in children and adolescents. In addition, some patients required drug discontinuation for intolerable side effects regarding the gastrointestinal tract. Both quinagolide (CV), at doses ranging from 0.075-0.6 mg/day, or cabergoline (CAB), at doses ranging from 0.5-3.5 mg/week orally, two selective DA receptor subtype-2 selective agonists, have been reported to be effective in reducing PRL secretion and tumor size in most adult patients with prolactinoma, even in those previously shown to be poorly responsive or intolerant to BRC (47). Cabergoline, is more effective and often better tolerated than bromocriptine.

Of our 50 cases (47), cabergoline induced normalization of PRL levels in all but 3 cases. Two of the three patients had large extrasellar macroprolactinomas (tumor volume of 4579 mm3 and 1983 mm3 respectively) with baseline PRL levels of 3300 μg/L and 1700 μg/L, respectively that progressively decreased but did not normalize after 2-7 years of treatment period. Tumor shrinkage by 93.2% and 54.5% was obtained in both patients. The latter patient had a microprolactinoma (tumor volume=123.6 mm3) with a baseline PRL levels of 500 μg/L that progressively decreased up to 88 μg/L at the last follow-up after 6 years of treatment and achieved tumor shrinkage by 53.9% (47). Only one case of pituitary apoplexy following cabergoline treatment in a young patient has been reported so far (60). Twelve of our 50 patients (one with enclosed macroprolactinoma and 11 with microprolactinoma) achieved the disappearance of the tumor so that were withdrawn from treatment (61).
In our former series, tumor shrinkage was observed in most patients with macroadenoma and even in some with microprolactinoma (Fig.10). The easy weekly administration makes CAB an excellent therapeutic approach to children/adolescents with prolactinoma. Cabergoline has been reported to be tolerated, even at rather high doses (62). The only relevant safety issue to be considered in patients treated with cabergoline is a recent alarm on a possible consequent cardiac valve derangement (63). This phenomenon appears in patients with Parkinson's disease, who are older and require higher doses of the drug than the patients with prolactinomas (35). Anyhow, this aspect deserves some attention and dedicated observational studies are ongoing. In patients with tumors resistant to dopamine agonists as well as in those showing severe neurological symptoms at diagnosis surgery is indicated ; radiotherapy, should be limited to the cases with aggressive tumors, non responsive to dopamine agonists, because of the risk of neurological damage and hypopituitarism later in the lives of these patients (48).

ACTH-secreting adenomas

Between 11 and 15 years of age, ACTH-secreting adenomas are the most frequent cause of adrenal hyper-function and the second most frequent pituitary adenoma after prolactinomas (8,28,30). A macroadenoma is rarely the cause of Cushing's disease (CD) in children (64,65, 66).

Clinical presentation and diagnosis

The clinical manifestations of CD are mostly the consequence of excessive cortisol production. The clinical presentation is highly variable, with signs and symptoms that can range from subtle to obvious (Table 1). The diagnosis is generally delayed since a decrease in growth rate may be the only symptom for a long time. Growth failure in CD may be due to a decrease of free IGF-I levels and/or a direct negative effect of cortisol on the growth plate (67,68). In a series of 50 children with CD, Magiakou et al. (68) found that obesity and growth retardation were the most frequent symptoms (in 90 and 83% of patients, respectively). Weight gain and stunted growth were the most frequent symptoms also in the series by Weber et al. (69) and Devoe et al. (70). The skin of the face is plethoric, and atrophic striae can be found in the abdomen, legs and arms. Muscular weakness, hypertension, and osteoporosis, especially of the spine, are common. Results on BMD or bone metabolism in children with CD have been reported only in some patients in a few studies (69,71). Consistent with the findings in adult patients, marked osteopenia was also found in affected children. The bone loss is more evident in trabecular than in cortical bone (72). As compared to patients with adult-onset disease, those with childhood-onset CD have a similar degree of bone loss at lumbar spine and similar increased bone resorption (73). In a study conducted in 10 patients with childhood-onset and 18 with adulthood-onset Cushing's disease (CD) Di Somma et al. found that BMD at lumbar spine was significantly lower than in sex and age-matched controls (Fig.11). Osteoporosis was found in 16 patients (57-1%) [8 adolescent (80%) and 8 adult (44-4%) patients] while osteopenia was found in 12 patients (42.8%) [2 adolescent (20%) and 10 adult (55-6%) patients] (73). Additionally, we have recently reported that two years of cortisol normalization improved but did recover bone mass and turnover neither in children nor in adult patients with CD (74).  This negative finding suggests that a longer period of time is necessary to restore bone mass after the cure of CD and, thus, other therapeutic approaches may be indicated to limit bone loss and/or accelerate bone recovery in these patients (70). In a recent study Lodish et al. (75) analyzed retrospectively 35 children with Cushing disease; in this patients, vertebral BMD was more severely affected than femoral BMD and this effect was independent of degree or duration of hypercortisolism. BMD for the lumbar spine improved significantly after TSS; osteopenia in this group may be reversible. Complete reversal to normal BMD was not seen. 

Hypercortisolism leads to decreased bone formation through direct or indirect inhibition of osteoblast function (76,77), while bone resorption is normal or increased in patients with CD (73,76-78). Hypercortisolism is known to be associated with loss of skeletal mass and can lead to increased vertebral fracture risk (79) It should also be noted that in children with CD the direct negative effect of hypercortisolism on bone formation is further worsened by concomitant hypogonadism and GH deficiency, both of which are associated with decreased BMD. Children with Cushing disease often have musculoskeletal weakness and can have decreased weight-bearing activity that may contribute to impaired BMD.
Children with CD may also have impaired carbohydrate tolerance, while overt diabetes mellitus is uncommon. Excessive adrenal androgens may cause acne and excessive hair growth, or premature sexual development in the first decade of life. On the other hand, hypercortisolism may cause pubertal delay in adolescent patients. Peculiarly, young patients with CD may present neuropsychiatric symptoms which differ from those of adult patients. Frequently they tend to be obsessive and are high performers at school.
The differential diagnosis of CD includes adrenal tumors, ectopic ACTH production, and ectopic CRH-producing tumors. However, ectopic ACTH secretion is extremely rare in the pediatric age. Among a large series including 306 cases with pediatric and adult Cushing's syndrome investigated at the St. Bartholomew's Hospital in London, 32 had ectopic ACTH syndrome of whom only 1 was in the pediatric age (64). This child was discovered as having a bronchial carcinoid tumor approximately 7 yrs after the first diagnosis of CD (69).
In a child/adolescent with suspected CD the diagnosis is based on measurement of basal and stimulated levels of cortisol and ACTH. Measurement of 24-h urinary free cortisol is elevated, and a low dose of dexamethasone (15 μg/Kg) at midnight does not induce suppression of morning serum cortisol concentrations as in normal subjects (64). Loperamide, an opioid agonist, lowers cortisol secretion and has been proposed as a reliable screening test for hypercortisolism in children and adolescents (80). Suppression of the spontaneous circadian variations of serum cortisol is another feature of CD. Suppression of cortisol by more than 50% after high dose dexamethasone (150 μg/Kg) given at midnight will confirm that hypercortisolism is due to an ACTH-secreting pituitary adenoma (80). Midnight salivary cortisol measurements have been suggested as an alternative non-invasive screening test in the diagnosis of CS in adults (81) but is not practice use this method.
All patients should undergo pituitary MRI with the administration of gadolinium, but since ACTH-secreting pituitary adenomas are significantly smaller than all other types of adenomas, often having a diameter of 2 mm or less (82), pituitary MRI may fail to visualize the tumor. In most instances the diagnosis of CD can be made by initial clinical and laboratory data (Fig.12). Bilateral inferior petrosal sinus sampling has a high specificity, so that no patient with extra-pituitary Cushing's syndrome runs the risk of being submitted to trans-sphenoidal surgery, but it carries a significant number of false negative results (82). This procedure can also be technically difficult in children, and the risk of morbidity from surgery and/or anesthesia must be considered. Lateralization of the adenoma can be of better help for the surgeon than pituitary scanning (83). Therefore, bilateral venous sampling should only be performed in centers with wide experience in the technical procedure as well as in the interpretation of the results. If a patient without anomalous venous drainage patterns exhibits a lateralizing ACTH gradient of 2:1 or greater (84,85), removal of the appropriate half of the anterior pituitary gland will be curative in 80% of cases (82). Kunwar and Wilson (82) reported that in the presence of a negative surgical exploration, a guide to the probable location of the adenoma is invaluable, and under the right circumstances, a hemi-hypophysectomy is appropriate and successful in most cases.

Treatment strategy

Trans-sphenoidal adenomectomy is the treatment of choice for ACTH-secreting adenomas in childhood and adolescence. Surgical excision is successful in the majority of children, with initial remission rates of 70-98% and long-term cure of 50-98% in most studies (30,31,37,68-70,86-90). The success rate decreases when the patients are followed-up for more than 5 years (68-70), and the outcome cannot be predicted either by preoperative or immediate postoperative tests (70). The morbidity is low when the procedure is carried out by an experienced neurosurgeon. In a recent study successful surgery was found in 59% of 27 patients over a 21-year period, with a higher age favouring cure, as did an identifiable tumour seen at surgery and positive histology (91). Cure was also more likely to be achieved if the surgery is performed by an experienced neurosurgeon, in analogy with other studies performed in acromegaly (92).
Trans-sphenoidal microsurgery is considered successful when it is followed by remission of signs and symptoms of hypercortisolism and by normalization of laboratory values. Surgery is usually followed by adrenal insufficiency and patients require hydrocortisone replacement for 6-12 months. After normalization of cortisol levels, resumption of normal growth or even catch-up growth can be observed. Generally, final height is compromised compared to target height (70,93). Johnston et al. (94) have, however, reported that some children do achieve a normal final stature. However, even if catch-up and favorable long-term growth can be achieved after treatment for Cushing's disease, post-treatment GH deficiency is frequent (95). Lebrethon et al. (95) demonstrated that early hGH replacement may contribute to a favorable outcome on final stature (Fig.13). A re-analysis of this series confirmed that pediatric Cushing's disease patients achieve a normal final stature provided that replacement therapy including GH is correctly performed (96). Normal body composition is more difficult to achieve. Many patients remain obese and BMI SDS was elevated at mean interval of 3.9 years after cure in 14 patients (96).

The treatment modality in patients who have relapses after trans-sphenoidal adenomectomy is still controversial. Some authors recommend repeated surgery (68,97), while others favor radiotherapy (98,99). Radiotherapy with or without concomitant mitotane treatment may be indicated in patients with macroadenoma (99). Rarely, surgery may induce panhypopituitarism, or permanent diabetes insipidus (37), while hypothalamic-pituitary dysfunction is an early and frequent complication of radiation (70). Bilateral adrenalectomy may be the last therapeutic option in case of failure of both surgery and radiotherapy. Pharmacotherapy is less successful and only a very few cases have been reported so far. In a 6.2-year-old male patient with severe hypercortisolaemia and life-threatening complications of Cushing's disease not responsive to metyrapone and ketoconazole, low-dose intravenous infusion of etomidate, with dose titration according to serum cortisol levels, induced normalization of cortisol levels in (from 1,250 to 250 nmol/l) within 24 h (100). Greening et al. (100) thus suggested that combined etomidate and hydrocortisone therapy could be a potential safe approach in patients with very severe Cushing's disease to be treated before bilateral adrenalectomy. To note that pediatric Cushing's disease patients, in contrast with adult patients, do not completely recover from cognitive function abnormalities despite rapid reversibility of cerebral atrophy (101). No data are available on medical treatment with somatostatin analogs and dopamine agonists in children/adolescents with CD.

GH-secreting adenomas

GH excess derives from a GH-secreting adenoma in over 98% of cases. In adulthood, these adenomas are relatively rare with a prevalence of 50-80 cases/million, and an incidence of 3-4 new cases/million per year (102), while gigantism is extremely rare with approximately 100 reported cases to date (103). In childhood, GH-secreting adenomas account for 5-15% of all pituitary adenomas (28,103). In less than 2% of the cases excessive GH secretion may depend on a hypothalamic or ectopic GH releasing hormone (GHRH)-producing tumor (gangliocytoma, bronchial or pancreatic carcinoid), which causes somatotroph hyperplasia or a well-defined adenoma(102).

Clinical presentation and diagnosis

In adults, chronic GH and IGF-1 excess causes acromegaly, which is characterized by local bone overgrowth, while in children and adolescents it leads to gigantism. The associated secondary hypogonadism delays epiphysial closure, thus allowing continued long bone growth (Fig.14). However, the two disorders may be considered along a spectrum of GH excess, with principal manifestations determined by the developmental stage during which such excess originates (Table 1). Supporting this model has been the observation of clinical overlap between the two entities, with approximately 10% of acromegalics exhibiting tall stature (104), and the majority of giants eventually demonstrating features of acromegaly (105). In contrast with adults where there is an increased prevalence of cardiovascular, respiratory, neoplastic and metabolic complication (106-110), there is no report of similar complications in childhood. In our study we did not find any patient with hypertension, arrhythmias, diabetes or glucose intolerance; as aspected, however, some degree of insulin resistance and enhanced ß-cell function was observed in our patient at diagnosis (111). In a recent study conducted in six patients with gigantism, Bondanelli et al. showed that 33% of giant patients had left ventricular hypertrophy and inadequate diastolic filling, 16.7% had isolated intraventricular septum thickening and impaired glucose metabolism (112). In acromegaly clinical features develop insidiously and progressively over many years and the average delay between the onset of symptoms and diagnosis is approximately 6 years (113), while the presentation of gigantism is usually dramatic and the diagnosis is straightforward. All growth parameters are affected although not necessarily symmetrically. Mild-to-moderate obesity occurs frequently (103), and macrocephaly has been reported to precede linear and weight acceleration in at least one patient (114). All patients also had coarse facial features, disproportionately large hands and feet with thick fingers and toes, frontal bossing and a prominent jaw (103). In girls menstrual irregularity can be present (115) while glucose intolerance and diabetes mellitus are rare. Tall stature and/or acceleration of growth velocity was observed in 10 of 13 patients. Only one case of ketoacidosis has been reported so far (116). The diagnosis of acromegaly and gigantism is usually clinical, and can be readily confirmed by measuring GH levels, which in more than 90% of patients are above 10 μg/l (102). The oral glucose tolerance test (OGTT) is the simplest and most specific dynamic test for both the diagnosis and the evaluation of the optimal control of GH excess (102). In healthy subjects, the OGTT (75-100 grams) suppresses GH levels below 1 μg/l after 2 hours, while in patients with GH-secreting adenoma such suppression is lacking, and a paradoxical GH increase is frequently observed. GH excess should be confirmed by elevated circulating IGF-I concentrations for age and gender (117). The assay of IGF-I binding protein-3 is conversely not useful for diagnosis nor for the follow-up of the patients (118,119). The presence of different GH isoforms in patients with gigantism/acromegaly may represent a diagnostic problem (120). A greater sensitivity of the GH assay may facilitate the distinction between patients and normal subjects, as shown by the use of a chemiluminescence GH assay (121). It might help in demonstrating the persistence of GH hypersecretion after surgery or during medical therapy. In case of clinical and laboratory findings suggestive of a GH-producing adenoma, pituitary MRI must be performed to localize and characterize the tumor.

Treatment strategy

The objectives of treatment of GH excess are tumor removal with resolution of its eventual mass effects, restoration of normal basal and stimulated GH secretion, relief of symptoms directly caused by GH and IGF-1 excess and prevention of progressive disfigurement, bone expansion, osteoarthritis and cardiomyopathy which are disabling long-term consequences, as well as prevention of hypertension, insulin resistance, diabetes mellitus and lipid abnormalities that are risk factors for vascular damage (102). The currently available treatment options for acromegaly include surgery, radiotherapy, and pharmacotherapy suppression of GH levels. Currently, cure criteria are serum GH levels below 2.5 μg/l, glucose-suppressed GH levels below 1 μg/l together with age-normalized IGF-I levels (117). Trans-sphenoidal adenomectomy is a cornerstone in the treatment of GH-secreting tumors. In case of macroadenomas, particularly when they exhibit extrasellar growth, persistent postoperative hypersecretion of GH occurs frequently. In most surgical series, only about 60% of acromegalic patients achieve circulating GH levels below 5 μg/l (122-125), but the success score improves when the surgeon is specialized in pituitary surgery (122,123). In pediatric patients with gigantism, trans-sphenoidal surgery was found to be as safe as in adults (126).
Treatment with somatostatin analogs is very effective in patients with GH excess (127), although limited data are available in adolescent patients. Octreotide given subcutaneously in two patients was shown to inhibit GH levels and reduce growth velocity (128,129). Of interest, in adolescents, as in adults, we observed tumour shrinkage by 30% on average after first-line treatment with somatostatin analogues. Whether this treatment has facilitated the subsequent surgical approach in this series could not be ruled out because of the limited number of cases studied. Treatment was tolerated very well by all patients (111)
Radiation therapy is rarely applied to pediatric patients, as radiation-induced damage of the surrounding normal pituitary tissue results in hypogonadism, hypoadrenalism or hypothyroidism in most patients within 10 years (130). Complications such as optic nerve damage, cranial nerve palsy, impaired memory, lethargy and local tissue necrosis have been reduced thanks to improved precise isocentric simulators and accurate dosing techniques. However, at least in adult patients normalization of IGF-I levels has been reported to occur rarely (131,132), even if results are controversial (133,164).
Additional pharmacological therapy consists of dopaminergic compounds such as BRC, CV or CAB (135). As most patients had concomitant hyperprolactinaemia, combined treatment with dopaminergic compounds such as BRC or CAB, and somatostatin analogues, may be necessary. The long-term treatment s.c. OCT plus BRC was tested in one child and was proven to be safe (136). In another case of a 15 yr old girl with a mixed GH/PRL-secreting adenoma (137), OCT-LAR (at the dose of 20 mg/28 days) combined with CAB (at the dose of 0.5 mg twice/week) normalized serum GH and IGF-I levels, and decreased growth rate from 12 cm/yr to nearly 2.5 cm/yr (Fig.14).  In seven of the eight hyperprolactinaemic patients included in our study, combined treatment with OCT plus BRC or LAR or LAN plus CAB was effective and well tolerated by all patients. Only two patients (15-4%) of the entire series still presented with active acromegaly after treatment with surgery and pharmacotherapy with somatostatin analogues plus dopamine-agonists (111).  The GH receptor antagonist pegvisomant is a very potent drug recently introduced in the clinical practice. In patients with resistant acromegaly, the use of the GH-receptor antagonist pegvisomant was followed by normalization of IGF-I levels in more than 80% of patients (138-140). However, there are no data related to pediatric patients. In a 12-year-old girl with tall stature (178 cm), bearing a GH/PRL-secreting macroadenoma inoperable since tumor tissue was fibrous and adherent to the optical nerves, the GH receptor antagonist at a dose of 20 mg/day completely normalized IGF-I levels (141).

TSH-secreting adenomas

This tumor type is rare in adulthood and even rarer in childhood and adolescence with only a few cases reported so far. It is frequently a macroadenoma presenting with mass effect symptoms such as headache, visual disturbance, together with variable symptoms and signs of hyperthyroidism (Table 1). TSH-secreting adenomas must be differentiated from the syndrome of thyroid hormone resistance (142). In most cases, the classical criteria of lack of TSH response to TRH stimulation, elevation of serum α-subunit levels, and a high α-subunit/TSH ratio along with a pituitary mass on MRI, are diagnostic of TSH-secreting adenoma (142).

Treatment strategy

Trans-sphenoidal surgery is the first treatment approach to these tumors. However, since the majority of these adenomas are macroadenomas, which tend to be locally invasive, surgery alone fails to normalize TSH and thyroid hormone levels in most cases. In adults, radiotherapy is recommended as routine adjunctive therapy when surgery has not been curative (142). However, due to the high frequency of post-radiotherapy hypopituitarism, in children pharmacotherapy is the preferred second choice. There is very little success with dopamine agonists for treatment of these tumors (135). In contrast, therapy with somatostatin analogs normalizes TSH levels in the majority of patients, and tumor shrinkage occurs in approximately half of cases (143-146). Chronic treatment with SR-lanreotide reduced plasma TSH and normalized fT4 and fT3 levels, suggesting its use in the long-term medical treatment of these adenomas (146).

Clinically nonfunctioning adenomas

FSH- and LH-secreting tumors with a clinical picture of hormone hypersecretion are very rare (147,148). The majority of FSH/LH-producing adenomas are clinically asymptomatic. Nonetheless, there are in vitro evidence that most of these tumors synthesize glycoprotein hormones or their subunits (147,148). In adults they represent 33-50% of all pituitary tumors, while in pediatric patients they account for less than 4-6% of cases (27,30,32,35). In a study, 5 out of 2288 patients treated at Hamburg University between 1970-1996 were diagnosed to bear a clinically nonfunctioning adenoma (149). The clinical presentation included visual field defects, headache and some degree of pituitary insufficiency since invariably all patients had a macroadenoma (Table 1). In the pediatric population, these adenomas need to be differentiated from other sellar/para-sellar masses such as cysts, craniopharyngioma and dysgerminoma. Therefore, the MRI of the sella and parasellar structure is the basic step in the diagnosis. Other pituitary hormone deficiencies are commonly associated with this adenoma hystotype, whereas diabetes insipidus occurs less frequently. A modest hyperprolactinemia can also be present due to pituitary stalk compression. All these conditions should be diagnosed and treated appropriately.

Treatment strategy

The first approach to these adenomas is trans-sphenoidal surgery to remove tumor mass and decompress parasellar structures. As in the other adenoma histotypes, surgery has a low morbidity and leads to an improvement of visual symptoms in the majority of cases. The recent development of the endoscopic endonasal unilateral transsphenoidal approach to the pituitary (150-153), which has the same indications as the conventional transsphenoidal microsurgery, overcomes many of the potential problems tied to the surgical route, thanks to its minimal invasiveness. This procedure encompasses no sublabial aggression nor any fracture of the facial bones with dental or naso-sinusal complications. Furthermore, a wider surgical vision of the operating field is obtained, which potentially improves the likelihood of a better and safer tumor removal. Furthermore, this procedure requires a shorter hospitalization, permits a rapid recovery of the child (154), and allows to maintain the neuroendocrine-pituitary integrity, with ensuing normal growth. This approach can also be safely used for the surgical removal of remnant pituitary tumors (153). After surgery these patients partially recover from hypopituitarism. Postoperative radiotherapy is applied in patients with subtotal tumor removal to prevent tumor re-growth and reduce residual tumors, but is burdened by a high prevalence of panhypopituitarism (155-157). Medical therapy has poor effects on clinically nonfunctioning adenomas (158). Very recently, positive effects of CAB were observed in some patients with α-subunit secreting adenomas, mostly in patients with tumors expressing high number of dopamine D2 receptors (159). A positive response to cabergoline associated with detection of dopamine receptors in vitro has been recently proven in clinically nonfunctioning adenomas (160).
Somatostatin analogs and dopamine agonists have not been tested in children/adolescents with clinically nonfunctioning adenomas.

Conclusions

Craniopharyngiomas and adenomas are the most frequent lesions of the pituitary region in children and adolescents. While craniopharyngiomas are the most frequent cause of acquired hypopituitarism in children, pituitary adenomas are rare constituting less than 3% of supra-tentorial tumors. The most frequent tumor hystotypes are PRL-secreting and ACTH-secreting adenomas, while GH-, TSH-secreting and clinically nonfunctioning adenomas are very rare. The clinical presentation varies according to the tumor histotype, but stunted growth is a frequent sign of macroadenomas. Surgery is almost always the treatment of choice for both craniopharyngiomas and adenomas, with the exception of PRL-secreting adenomas which can be successfully managed using dopamine-agonists. Radiotherapy should be reserved to very aggressive tumors due to the very high incidence of subsequent hypopituitarism.