ABSTRACT

Central nervous system (CNS) tumors are the second commonest childhood malignancy, with 10% of these affecting the suprasellar and/or intrasellar regions. Survival has increased significantly over the last decade as a result of improved multimodality cancer therapies and better supportive care. Measurements of serum prolactin, α-fetoprotein, and β-hCG as well as baseline pituitary function tests are essential at diagnosis prior to commencement of any therapy. Craniopharyngiomas and low-grade gliomas account for most of these tumors, whilst other histological subtypes such as pituitary adenomas, germinomas, and hamartomas are rare. Non-neoplastic masses include pituitary hyperplasia and Rathke’s cleft cysts. Neurological syndromes and endocrine dysfunction are often present at diagnosis, and may be missed if not sought for. Post-diagnosis, endocrinopathies can evolve over decades secondary to tumor and/or treatment, necessitating long-term follow-up of such patients. Treatment of endocrine dysfunction is crucial not just to avoid the fatal consequences of untreated secondary adrenal insufficiency and/or diabetes insipidus, but also to improve quality of survival, and should be closely supervised by a pediatric endocrinologist with experience in the management of such patients. Growth hormone therapy in replacement doses in particular has not been shown to increase the risk of tumor recurrence. The “hypothalamic syndrome”, including variable hypothalamic dysfunction (e.g., sleep-wake cycle disturbances, temperature dysregulation, adipsia, and behavioral disorders) and hypothalamic obesity, is a common and as yet untreatable sequela of both tumor and treatment. The latter is caused by dysregulation of a network anorexigenic and orexigenic hormone signals which is only beginning to be elucidated. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG.

INTRODUCTION

Central nervous system (CNS) tumors are the second commonest childhood malignancy after leukemias, accounting for 25% of cancers in children <15 years of age with an annual incidence rate of 35 cases/million/year (1–4). As with all childhood cancers, their incidence is gradually increasing worldwide (1,2,5), an effect largely attributed to improvements in diagnosis and tumor registration (6–8), and more recently campaigns such as the UK HeadSmart project aimed at increasing awareness of pediatric brain tumor symptoms (http://www.headsmart.org.uk/) (9). Concurrently, 5-year survival for CNS tumors has increased much more steeply from 57% to 65% in the last decade (~95% in low-grade gliomas) as a result of improved multimodality cancer therapies and better supportive care (10–12).

However, while survival is high, increasingly intensive treatment strategies aimed at improving cure in a small minority can conversely cause a higher toxicity burden in the larger majority, with a rapidly accruing cohort of survivors faced with reduced quality of life due to late and evolving multi-organ toxicities (13–15). Over 40% of these chronic morbidities (“late effects”) are severe, disabling or life-threatening (16), and more than 80% of CNS tumor survivors develop at least one endocrinopathy, most frequently growth hormone deficiency (17). Indeed, suprasellar tumors have been found to be the commonest cause of hypothalamo-pituitary dysfunction in adult cohort studies (18,19). However, when compared with adult CNS tumors, pediatric tumors tend to be more curable, and the early presentation of some tumors (e.g., craniopharyngiomas, primitive neuroectodermal tumors (PNET)), and their association with mutations in neural development genes blur the delineation between congenital malformations and neoplasia (20–22).

Tumor location and histology is distinctly age-dependent: 30% of tumors under the age of 14 years are infratentorial (medulloblastomas, posterior fossa juvenile pilocytic astrocytomas, and ependymomas), whilst 26% and 16% of tumors diagnosed in young adulthood (15 to 24 years) are supratentorial or suprasellar respectively (non-pilocytic astrocytomas, other gliomas, pituitary adenomas, and germinomas) (4,23). Supra- and intrasellar tumors constitute 10% of all pediatric CNS tumors (23,24) and their close proximity to the vital hypothalamo-pituitary axis (HPA) increases the risk of important endocrine dysfunction. This may occur secondary to tumor mass effect and/or treatment, and can therefore be manifest at presentation or evolve subsequently during or after completion of oncological therapies. Dissecting the effect of tumor from treatment on endocrinopathies diagnosed after commencement of therapy is particularly complicated. We aim here to (1) outline the epidemiology, clinical features, and management of common pediatric suprasellar tumors not readily addressed in other chapters, (2) examine the common clinical neuroendocrine presenting features and (3) summarize common themes in the neuroendocrine late effects observed at follow-up of these patients.

THE DIFFERENTIAL DIAGNOSIS OF PEDIATRIC SUPRA- AND INTRASELLAR MASSES

The definitive diagnosis of pediatric suprasellar and intrasellar masses is crucial, as therapeutic strategies differ markedly depending on histological subtype. However, a tissue diagnosis may not always be possible due to their location, as even minor procedures such as biopsies can lead to life-threatening endocrinopathies such as diabetes insipidus (DI) (25). Biochemical measurements of serum prolactin (PRL), α-fetoprotein (AFP), and β-human chorionic gonadotrophin (β-hCG) to aid the diagnosis of prolactinomas and secreting germinomas respectively are therefore absolutely essential prior to commencement of any therapy.

Craniopharyngiomas

Figure 1.

T₁-weighted MRI images of a craniopharyngioma demonstrating the coexistence of solid, cystic and calcified components with the tendency for multiple progressions over seven years. (a) After initial endoscopic cyst fenestration and ventriculoperitoneal shunt insertion, (b) after first transcranial debulking, (c) first cystic progression, (d) after first cyst drainage via reservoir, (e) second cystic progression, (f) after second transcranial debulking, (g) after adjuvant radiotherapy and third cystic progression, (h) after second cyst drainage via reservoir, (a) after fourth cystic & solid progression, (j) after complete resection.

Craniopharyngiomas are by far the commonest suprasellar tumor of childhood, accounting for up to 50-80% of masses in this region (24,26–28) and 1.5-11.6% of all pediatric CNS tumors (3,24,26,29,30). There is a bimodal age distribution in incidence, with the peak incidence in childhood occurring between the ages of 5-14 years at 1.4 cases/million/year (29,31). They are benign tumors originating from the embryonal epithelium lining Rathke’s pouch and are almost invariably adamantinomatous in childhood, characterized by the presence of intratumoral calcifications (32). Over-activation of the Sonic hedgehog (SHH) and Wnt/β-catenin pathways, both important in both pituitary stem cell development and carcinogenesis, have been shown to be key to their formation (20,21), but they occur typically sporadically, with only one case report of familial adamantinomatous craniopharyngiomas occurring in a consanguineous pedigree reported in the English literature (33). Contrastingly, papillary craniopharyngiomas are found almost exclusively in adults and harbor the BRAF V600E mutation instead (34).

Symptoms related to hypothalamo-pituitary dysfunction, such as weight gain, growth failure, prolonged recovery from infections, and abnormalities of puberty are often under-recognized but in fact constitute the third commonest group of clinical findings at diagnosis, after symptoms related to raised intracranial pressure (e.g., headaches, vomiting) and visual deterioration (22,35–47). Radiologically, 65-93% of these tumors are calcified but a plain X-ray or computerized tomography (CT) scan may be required to demonstrate this. The coexistence of solid, cystic, and calcified structures on neuroimaging, as well as the characteristic cholesterol crystals seen under microscopy of the “engine fluid” aspirated surgically from cystic components are so highly suggestive of the diagnosis that histological confirmation from biopsies of solid components may be unnecessary, particularly as this may further compromise hypothalamo-pituitary function (32,48). Anatomically, 75% of craniopharyngiomas are suprasellar with an intrasellar extension, 20% are exclusively suprasellar, and 5% are exclusively intrasellar, with over 50% involving the hypothalamus and nearly one-third invading the floor of the third ventricle (26,37,44).

Due to their location, a significant proportion of these tumors are not completely resectable, but their relative rarity, high rates of survival, and benign histology have precluded them from pan-European randomized trials, resulting in a lack of agreement on the optimal treatment strategy. Most recently, the first evidence- and consensus-based national UK guideline for the management of craniopharyngiomas in children and young people has been published by the UK Children’s Cancer and Leukemia Group (CCLG), with endorsement from the Royal College of Pediatrics and Child Health (RCPCH) and British Society of Pediatric Endocrinology & Diabetes (BSPED) (49).Importantly, these guidelines advocate a more conservative approach to the degree of surgical resection in the presence of significant hypothalamic involvement in order to minimize further damage to the hypothalamo-pituitary axis (39,50,51), balanced against the need to relieve symptoms of raised intracranial pressure, preserve vision, and provide long-term control and reduced recurrence rates (49,52,53). The use of adjuvant radiotherapy in combination with subtotal tumor resection has been shown to achieve survival rates which are on par with complete tumor resection (5-year progression-free survival 73-100% vs 73-82%), with the potential for less neuroendocrine dysfunction (54–56). More recently, the use of proton beam therapy has increased, with equivalent survival outcomes to conventional radiotherapy, but there remains the issue of insufficient follow-up data to ascertain its long-term toxicity profile (57,58). Experience with systemic or intracystic chemotherapy, intracystic interferon, and radioisotope instillation of ³²P or ⁹⁰Y have been met with conflicting success and cannot therefore be currently recommended as primary treatment approaches in children (59–62). Ultimately, despite high long-term overall survival (80% at 30 years), (37) up to 98% of survivors experience dysfunction in at least one hypothalamo-pituitary axis with high rates of morbid obesity (45,63).

Low-grade Gliomas (LGGs)

Figure 2.

T₁-weighted MRI image demonstrating appearances of a large, lobulated optic pathway astrocytoma with hydrocephalus and widespread leptomeningeal dissemination affecting the brainstem, cerebellum, and spinal cord.

LGGs account for >40% of all CNS tumors and are thus the commonest pediatric intracranial tumor (3,8). The optic pathway, hypothalamus, and suprasellar midline are the second most frequent location for LGGs (30-50%) after the cerebellum, cerebral hemispheres, and brainstem (12,64). Even in the suprasellar region they are the second commonest pediatric tumor after craniopharyngiomas, and are similarly regarded as benign (grade I or II), the vast majority being juvenile pilocytic astrocytomas (65). The genetic tumor predisposition syndrome neurofibromatosis type 1 (NF-1) is present in 10-16% of cases, whilst 15% of asymptomatic NF-1 children will have LGGs on neuroimaging. NF-1-associated tumors more often originate from the optic nerves (70%) than from the hypothalamochiasmatic area (27-40%) and tend to a more indolent course (11,12,64,66–69). Mutations involving KIAA1549, BRAF and Ras proto-oncogenes are associated with pilocytic astrocytomas and disruptors targeted at these pathways form the basis of current clinical therapeutic trials (70–72). Similar to craniopharyngiomas, the commonest symptoms at diagnosis are related to visual changes or raised intracranial pressure, with disorders of the LH/ FSH axis being the most prevalent endocrinopathy at presentation (25,66,73–75). In infancy, hypothalamic LGGs can present with diencephalic syndrome (see below) (11,76–78), which significantly increases the risk of future neuroendocrine dysfunction (79).

Complete tumor resection has been shown to be a favorable risk factor for survival (12,64) but suprasellar and/or optic pathway tumors cannot be completely resected without causing major visual and neuroendocrine morbidity. Treatment trials have thus focused on medical strategies, with radiotherapy being delayed in favor of chemotherapy in young children due to concerns of cognitive dysfunction (80), subsequent primary cancers (SPCs) (81,82) and radiation-induced vasculopathies (83), despite showing superior 5-year progression-free survival rates (65% vs. 47%) (11). However, to date none of the previous international treatment trials – LGG1 (1997-2004) or LGG2 (2005-2010) – were randomized, these being purely observational studies aimed at improving visual outcomes but with little reported success (11,12,84). At the time of writing, the first randomized interventional study of chemotherapeutic strategies (LGG3) is being designed with careful long-term prospective measurements of visual and neuroendocrine outcomes. More recently, tumors harboring BRAF mutations have been the target of MAPK/ERK kinase (MEK) and BRAF inhibitors such as trametinib and dabrafenib (72,85–87), although these can still lead to various side effects including endocrinopathies(88).

A 30-year survival analysis has revealed the extent of long-term neuroendocrine dysfunction affecting these patients with new endocrine deficits appearing up to 15 years post-diagnosis, and 20-year endocrine event-free survival approaching 20% (25). Hypothalamic tumor location is a more important independent risk factor for long-term anterior hypothalamo-pituitary deficits than radiotherapy exposure; however only surgical intervention (regardless of extent) has been shown to be independently associated with posterior pituitary dysfunction and life-threatening salt and water imbalances (25,64). Similar to craniopharyngiomas, overall survival is high (85% at 25 years), but ~80% of survivors experience at least one endocrinopathy (25,79).

Pituitary Adenomas

Figure 3.

T₁-weighted MRI image demonstrating appearances of a giant prolactinoma. There is obscuration of normal pituitary morphology due to the tumor arising from the pituitary gland itself.

Pituitary adenomas are rare in childhood, accounting for just 3% of all supratentorial tumors with an estimated annual incidence of 0.1 cases/million/year in children (89). The vast majority are functioning, with prolactinomas alone accounting for 50% of adenomas and 2% of all pediatric and adolescent intracranial tumors. Therefore, the measurement of plasma prolactin (PRL) may be diagnostic and is absolutely mandatory prior to planning surgery for any pituitary mass, as medical treatment alone may be entirely curative (90,91). ACTH- and GH-secreting adenomas are the next commonest, whilst TSH-secreting, gonadotrophin-secreting, and non-functioning adenomas are vanishingly rare (91–93).

A child with a pituitary adenoma may be the index case for a genetic tumor predisposition syndrome (up to 22%), particularly given their rarity, and therefore careful documentation of their family history and testing for multiple endocrine neoplasia type 1 (MEN1) and aryl-hydrocarbon receptor interacting protein (AIP) gene mutations are therefore paramount in all cases (94–96). Other genetic syndromes associated with pituitary adenomas that need to be considered are multiple endocrine neoplasia type 4 (CDKN1B), Carney complex (PRKAR1A), McCune-Albright syndrome (GNAS), SDH-related pituitary adenoma syndrome (SDHB, SDHC, SDHD), and DICER1 syndrome (97).

Investigation and management of pituitary adenomas depends on whether they are functioning or non-functioning, and in the case of the former, which hormones are being secreted in excess. Similar to craniopharyngiomas, an evidence- and consensus-based national UK guideline is being written for the management of pituitary adenomas in children and young people as a collaborative effort between the CCLG, RCPCH and BSPED.

PROLACTINOMA

Pituitary adenomas are classified as microadenomas (<1 cm), macroadenomas (>1 cm), and giant adenomas (>4 cm). In prolactinomas plasma PRL levels generally, but not exclusively, increase with tumor size. Hyperprolactinemia may also result from stalk compression by tumor mass (interrupting hypothalamic dopaminergic inhibition of PRL secretion) and antipsychotic medication but PRL concentrations are usually <2000 mU/l and patients rarely symptomatic (98). Laboratories should always screen for artefactual hyperprolactinemia due to macroprolactin, but levels >5000 mU/l are usually diagnostic and symptomatic. Occasionally, falsely low results can be due to interference by extreme hyperprolactinemia on antibody-antigen sandwich complex formation, a phenomenon known as the hook effect. In cases of large tumors, samples should therefore be diluted 100-fold and repeated for confirmation (99). Clinical presentation varies according to the size of tumor, gender, and pubertal status, with girls usually experiencing galactorrhea, pubertal delay, or amenorrhea and boys presenting later with larger, more aggressive tumors with raised intracranial pressure (90).

Given the paucity of good quality outcome data in children, treatment guidelines follow those for adults (53,91), recommending dopamine agonists (DAs) as first line, ideally cabergoline due to its high efficacy and tolerability (98). Starting doses, dose escalation and duration of therapy in children remain undefined and are critical questions given the potential for more aggressive disease and cardiac valve abnormalities with long-term cumulative exposure (100). Surgery should be reserved for those cases resistant to DAs or for neurosurgical emergencies (e.g., neuro-ophthalmic deficits, pituitary apoplexy) and both trans-sphenoidal and transcranial approaches should be considered by an experienced pediatric neurosurgeon. Radiotherapy has usually been reserved for treatment failures in view of the presumed risk of post-treatment endocrine morbidity and second primary cancers. However, the former may have been overestimated in view of the high incidence of endocrinopathies already present at diagnosis (101), and therefore this treatment modality should be considered earlier and prior to other more experimental treatments such as temozolomide chemotherapy (98). As with other hypothalamo-pituitary tumors, long-term neuroendocrine and secondary cardiovascular morbidity is significant (102).

CORTICOTROPHINOMAS

The age distribution for corticotrophinomas is younger than that of prolactinomas (where the incidence increases in adolescence and young adulthood), with Cushing disease accounting for the vast proportion of Cushing syndrome in children aged >5 years, and >70% of pituitary adenomas in the prepubertal age group (103,104). These tumors are nearly always microadenomas. Common presenting features include weight gain with linear growth arrest or short stature, change in facial appearance, fatigue, striae, hirsutism, emotional lability, hypertension, acne, headaches, or psychosis (104–106). Diagnosis is achieved by firstly screening for Cushing syndrome indicated by a raised urine free cortisol (sensitivity 89%) or midnight cortisol concentration of >50 nmol/l (sensitivity 99%, specificity 20%). This is then followed by a low-dose (sensitivity 100%, specificity 80%) then high-dose (sensitivity 94%, specificity 70%) dexamethasone suppression test (104,107–111). CRH-stimulated bilateral inferior petrosal sinus sampling (BIPSS) may help successfully localize the position of the microadenoma (104,105). Transsphenoidal resection is the first-line treatment of choice, superseding bilateral adrenalectomy which carries a risk of post-operative Nelson syndrome (112). Cure rates are 45-78% with nearly 40% requiring adjuvant radiotherapy (113–115).

SOMATOTROPHINOMAS

8-15% of all pituitary adenomas in patients <20 years of age secrete GH, with a significant proportion co-secreting PRL and TSH (103,116). Genetic syndromes associated with somatotrophinomas include MEN-1 (MEN1), Carney complex (PRKAR1A), McCune-Albright syndrome (GNAS), and familial isolated pituitary adenoma (FIPA, AIP) syndrome (97). Due to the absence of complete epiphyseal fusion, in childhood and adolescence, somatotrophinomas present with pituitary gigantism rather than acromegaly. Tall stature and increased growth velocity however can still be associated with other acromegalic features such as mild obesity, macrocephaly, acral enlargement, frontal bossing, and macrognathia (93,117). Investigations reveal high random GH and IGF-1 concentrations, loss of GH pulsatility, and failure of GH suppression to an oral glucose tolerance test (87). Like corticotrophinomas, transsphendoidal resection is the treatment of choice but a significant proportion of patients require adjuvant medical therapy with somatostatin analogues (octreotide, lanreotide), dopamine agonists (cabergoline, bromocriptine), or the GH receptor antagonist pegvisomant (118). Radiotherapy has been used with limited effect (119).

Germ Cell Tumors

Figure 4.

T₁-weighted MRI image demonstrating the appearance of a contrast-enhancing suprasellar β-hCG-secreting germinoma in a patient who presented with central diabetes insipidus.

Germ cell tumors (GCTs) are tumors arising from primordial germ cells normally sited in the testes and ovaries and can be subclassified into germinomatous (GGCT, usually non-secreting but can occasionally produce βhCG) and non-germinomatous germ cell tumors (NGGCT). NGGCTs and can be further classified into yolk sac tumors (secreting α-fetoprotein (AFP)), choriocarcinomas (secreting βhCG), and embryonal carcinomas. In contrast to craniopharyngiomas and LGGs, intracranial GCTs account for just 3-4% of all primary pediatric and young adult CNS tumors <24 years (23,120). There is a clear peak in incidence in adolescence and young adulthood, with age-adjusted incidence rates rising from 0.9 cases/million/year in patients <10 years to 1.3-2.1 cases/million/year in patients aged 15-24 years (23,120). Boys are affected nearly three times as often as girls, and this sex distribution is magnified in adolescence (male: female ratio of >8:1) (23). GCTs are also the commonest CNS tumor in Klinefelter and Down syndromes (121). Diabetes Insipidus (DI) and gonadotrophin-independent precocious puberty (due to βhCG acting on the LH receptor) are common findings at diagnosis and present in 30-50% and 11-12% of patients respectively. Unlike NGGCTs, GGCTs can grow indolently (if at all), meaning that both clinical and radiological features can often be subtle at onset, and delays in diagnosis up to 21 years have been reported (122–124).

Histologically, intracranial GCTs resemble their gonadal counterparts (ovarian teratoma or testicular seminoma) and account for 34% of all such tumors (125). They have a particular predilection for the pineal gland (37-66%) and suprasellar region (23-35%), such that synchronous (bifocal) pineal and suprasellar tumors are pathognomonic. Both GGCTs and NGGCTs are extremely chemo- and radiosensitive, and their propensity to metastasize throughout the cerebrospinal fluid (26,121,126) has meant that whole neuraxial (craniospinal) irradiation has been standard therapy for decades, with overall and progression-free survival rates approaching 100% (119). Chemotherapy alone has been shown to result in inferior survival (127), and more recent attempts to reduce the irradiation field with adjuvant chemotherapy in an effort to preserve cognitive function have shown little reduction in overall survival (121,128,129). The latest SIOP CNS GCTII however aims to reduce the radiation dose and field by stratifying treatment strategies between NGGCT and GGCTs, and based on the absence or presence of metastatic disease (https://www.skion.nl/workspace/uploads/2_siop_cns_gct_ii_final_version_2_15062011_unterschrift_hoppenheit.pdf). As for other suprasellar tumors, the rate of post-treatment endocrine morbidity is significant, with 50-60% of patients having at least one endocrinopathy (122).

Hypothalamic Hamartomas

Figure 5.

T₁-weighted MRI image demonstrating the appearances of a pedunculated hypothalamic hamartoma (arrowheads) arising from the floor of the third ventricle in a patient who presented with central precocious puberty. The pituitary morphology is otherwise normal.

Hypothalamic hamartomas are extremely rare congenital (rather than neoplastic) malformations consisting of grey matter heterotopia in the tuber cinereum and inferior hypothalamus (24,26,130). Their true prevalence is unknown but is estimated to occur in between 1 in 50,000 – 1 million individuals (131–133). Symptom onset occurs in infancy to early childhood, with the mean age of first seizures occurring between 6 weeks – 4.5 years (133–136). The triad of epilepsy (usually gelastic (laughing) or dacrystic (crying) seizures), central precocious puberty, and developmental delay is classic with the seizure semiology eventually evolving into multiple, more severe seizure types (130). Rarely, they are associated with Pallister-Hall syndrome, an autosomal dominant disorder characterized by polydactyly and other midline defects (imperforate anus, bifid epiglottis, panhypopituitarism and dysmorphic facies) (132,137), or with SOX2 mutations (138).

The intrinsic epileptogenicity of these lesions (139,140), the trend towards evolving seizure semiology, the worsening of behavioral and psychiatric co-morbidities, and the general failure of anti-epileptic drug therapy has led clinicians to explore the options of surgical or stereotactic radiosurgical resection despite their deep-seated location, with variably reported success in the remission of seizure activity and behavioral disturbances, but more modest improvements in cognitive function (130,131,141–143). Li et al.'s (144) case series reported successful remission of central precocious puberty (CPP) and little, if any, late-onset endocrinopathy; but a larger cohort study by Freeman et al. (145) suggested that clinically silent endocrine dysfunction (particularly GH and TSH deficiency) is common both at diagnosis and postoperatively. Transient posterior pituitary dysfunction leading to DI and the syndrome of inappropriate antidiuretic hormone secretion (SIADH) has also been described (145,146). One adult cohort study corroborates these findings, showing that >1/3 of these patients had endocrine dysfunction and approximately 2/3 experienced excessive weight gain postoperatively (147). More recently laser induced thermal therapy (LiTT) of these lesions has shown promising results with regards to seizure control, with little late onset additional endocrinopathies (148,149).

Langerhans Cell Histiocytosis (LCH)

Figure 6.

T₁-weighted MRI image demonstrating the appearances of a contrast-enhancing suprasellar LCH lesion. There is a small anterior pituitary and absent posterior pituitary bright spot in keeping with the known panhypopituitarism (including central DI) present at diagnosis.

LCH (previously “histiocytosis X”) is one of the three major histiocyte disorders, and involves clonal proliferation of bone marrow-derived dendritic antigen-presenting (“Langerhans”) cells which accumulate in various organs (150). It is a rare disease with an incidence of 2.6-8.9 cases/million/year, the majority presenting in infancy (median age at diagnosis 2-3.8 years, incidence at age <1 year 9.0-15.3 cases/million/year vs. age >5 years 0.7-4.5 cases/million/year) with no sex predilection (151–154). The variability in organ involvement causes a spectrum of clinical features ranging from a single self-healing cutaneous lesion to fatal multiorgan disease, particularly if the liver, spleen, lungs, and hemopoietic system (the “risk” organs) are involved (150). Multisystem involvement is present in 27-56% of cases, of which 28-80% have “risk” organ involvement (151–153,155,156). LCH can thus be considered a primary hematological disorder which, in a proportion of cases, infiltrates the CNS, although its etiology, whether neoplastic or reactive, remain poorly understood (155). More than half of biopsied lesions contain BRAF mutations (157).

In the CNS, the hypothalamo-pituitary region is involved in up to 25% of cases, which almost invariably leads to DI (previously known as Hand-Schuller-Christian disease if associated with orbital and bony lesions) (151,152,154,158,159). Commonly associated radiological findings include thickening of the pituitary stalk with progression to space-occupying tumors and an absence of the posterior pituitary bright spot (159). Indeed, LCH is the commonest underlying diagnosis in patients with central DI and an intracranial mass, occurring in 70% of this cohort (160). The presence of multisystem involvement, particularly if involving “risk” organs, craniofacial bones, gastrointestinal tract, skin, or genitalia) is a particular risk factor for DI (159,161).

Treatment is dependent on the number of organs involved and may range from biopsy/curettage, intralesional steroids, indomethacin, and radiotherapy/UV phototherapy for single bone and cutaneous lesions to systemic chemotherapy with steroids and vinblastine for multisystem disease (155,162,163). Refractory cases have been treated with cytarabine, cladribine, clofarabine, hemopoietic stem cell transplantation, or BRAF inhibitors (164–168). Notably, no treatment protocol has been shown to reverse existing or prevent future DI or other endocrinopathies (159), though current therapeutic recommendations are aimed at preventing disease progression and limiting endocrinopathy with prolonged, low-dose systemic chemotherapy (155,169–171). Overall, 5-year survival remains relatively high at 71-95%, but 3-25% of patients experience at least one endocrinopathy (particularly GH deficiency), with no current chemotherapeutic regimens showing superior overall- or endocrine event-free survival (151,156,158,161).

Pituitary Stalk Thickening

Figure 7.

T₁-weighted MRI image illustrating the appearances of a contrast-enhancing thickened pituitary stalk lesion (arrow) and an absent posterior pituitary bright spot in a patient presenting with central DI. The differential diagnosis included germinoma and LCH. However, approximately one year after diagnosis, the pituitary stalk lesion resolved completely, although the patient has been left with GH deficiency and central DI.

A thickened pituitary stalk (TPS) may be discovered either as part of the evaluation of a patient presenting with central DI, visual impairment, or other endocrine dysfunction or incidentally on neuroimaging performed for other purposes. It is discussed here as it is an important differential for germ cell tumors and Langerhans cell histiocytosis (LCH), resulting frequently in diagnostic and management dilemmas, due to a number of reasons:

1.

There is no clear consensus as to what constitutes abnormality for children; previous adult studies have shown that the 95^th centile for the transverse dimensions of the infundibulum at the optic chiasm and pituitary insertion are 4.21-4.35 mm and 2.69-2.89 mm respectively (upper limit 4.21-4.58 mm and 2.93-3.04 mm) (172,173). Raybaud and Barkovich suggest using a pediatric threshold thickness of 3.8 mm at the optic chiasm and 2.7 mm at the pituitary insertion for investigating further pathology, particularly if there are interruptions in the normal smooth tapering of the infundibulum from median eminence to pituitary insertion (174).

2.

The radiological appearances of a TPS, LCH and germinomas cannot be easily differentiated and there is substantial overlap (Table 2). The normal infundibulum lacks a blood-brain barrier and therefore always enhances with contrast, obscuring neoplastic processes. TPS is the commonest initial radiological finding in both LCH and germinomas, and concurrent absence of the posterior pituitary bright spot is inconsistent (123,175,176). Similarly, the two commonest causes of TPS in the pediatric age group are LCH and germinomas, accounting for 7-75% and 9-71% of TPS cases respectively (176–179). Other common causes of TPS in adults such as lymphocytic hypophysitis and neurosarcoidosis are rare in children (176).

3.

Biopsies of the TPS to obtain a definitive histological diagnosis can be inconclusive and lead to further substantial endocrine morbidity, including panhypopituitarism with DI, and are thus generally avoided (178).

4.

The interval from the time of initial symptoms to diagnostic MRI can be prolonged, particularly for germinomas (up to 21 years), occasionally with initially normal neuroimaging (123,124,180,181). An initially normal MRI does not therefore preclude an occult germinoma or other pathological process in the presence of idiopathic central DI, leading some authors to recommend serial 3-6 monthly scans and follow-up, although the duration of serial scanning is unclear (174). Additionally, there have been cases of occult germinomas masquerading as radiologically or even histologically diagnosed lymphocytic hypophysitis in children (182,183).

In an attempt to define which patients with isolated TPS are at risk of neoplasia and therefore require more intensive follow-up or biopsy, Robison et al. suggest risk factors such as the presence of DI (strongest risk factor), the coexistence of DI with anterior pituitary dysfunction or a progressive increase in infundibular size of >15% from baseline (178). Apart from size, no other particular MRI appearances have been found to be specific for pediatric-related tumor processes (184). Various proposed diagnostic pathways have been proposed for the management of TPS and idiopathic DI (178,184,185) but most recently a national consensus-based guideline has been developed in the UK by the CCLG, RCPCH and BSPED to help achieve a more consistent approach to this finding (186).

NEUROENDOCRINE DYSFUNCTION AT DIAGNOSIS OF HYPOTHALAMO-PITUITARY TUMORS

NEUROENDOCRINE DYSFUNCTION AFTER DIAGNOSIS AND/OR TREATMENT

Posterior Pituitary Dysfunction (PPD)

Posterior pituitary dysfunction can present itself in three ways – DI, SIADH, or cerebral salt-wasting syndrome (CSW), the latter attributed to hypersecretion of cerebral atrial natriuretic (ANP) and brain natriuretic peptides (BNP) in response to plasma volume expansion by ADH. The latter two syndromes are rare outside the context of an acute cerebral insult and are usually transient, whilst DI may be a presenting feature and/or a permanent post-operative deficit. The absence of a posterior pituitary bright spot on MRI is a relatively sensitive marker of a lack of neurohypophyseal integrity (275–277). DI does not develop after cranial irradiation in the absence of a hypothalamo-pituitary tumor or surgery to the area (25,99). Whilst PPD is the least common form of endocrinopathy, the rapid shifts from hyper- to hyponatremia in the acute setting can prove life-threatening, as evidenced by a recent retrospective cohort study of optic pathway LGGs with high survival showing showed that nearly 50% of the deaths that occurred were associated with uncontrolled PPD (25). This risk is further increased by coexistent ACTH deficiency, hypothalamic adipsia, and treatment with anti-epileptic medications, which have SIADH-like effects.

After hypothalamo-pituitary surgery, PPD presents as a well-described triphasic response in ADH secretion: firstly, immediate but transient DI up to day 2; secondly, SIADH from day 1-14; and finally, a second phase of DI, which is usually permanent if it persists beyond 21 days, the preceding SIADH is prolonged or severe, or if extensive surgery has been performed (278,279). This triphasic response is thought to result from necrosis of hypothalamic ADH-secreting magnocellular neurons and is seen more often in children than adults (23% vs. 14% in one craniopharyngioma study) (280). The three phases may also occur independently, and cerebral salt-wasting syndrome may coexist and complicate diagnosis and management. Dramatic changes in sodium concentrations can therefore occur with the inherent risk of seizures, cerebral edema and death; such patients require high intensity care with precise fluid management supervised by an experienced pediatric endocrinologist. The measurement of plasma and urinary arginine-vasopressin (AVP) may help differentiate between these different disorders, but these assays are not widely available and careful sample processing is required prior to analysis (281). More recently, measurement of plasma copeptin, the more stable by-product of cleavage of AVP from its carrier protein neurophysin II, is becoming more widely available and has been shown to be a more easily measurable, sensitive, and specific surrogate marker of AVP secretion (282–284).

Detailed management of these disorders is beyond the scope of this chapter, but can be summarized in the algorithm seen in Figure 8.

Figure 8.

Algorithm for the management of post-operative salt-water balance disorders (53).

CONCLUSIONS

Pediatric hypothalamo-pituitary tumors are uncommon, and may present with occult or unusual clinical features posing diagnostic dilemmas that incur treatment delays or necessitate prolonged MRI surveillance. Notwithstanding their generally high survival rates, tumor- or treatment-related neuroendocrine morbidity is very significant and not always simply reversible by hormone replacement therapy. Consequently, treatment decision-making should aim to preserve not only visual, but also hypothalamo-pituitary function. Pediatric endocrinologists and pituitary surgeons should be part of the decision-making multidisciplinary team, with radiological, visual, and biochemical assessments together aiding management planning. A detailed baseline endocrine assessment is paramount to both diagnosis and treatment and will ultimately improve long-term outcome monitoring, the clarification of tumor- and treatment-related consequences and management of lifelong morbidity. Given the potentially significant reduction in health-related quality of survival, lifelong, age-appropriate follow-up and management within a dedicated multidisciplinary neuroendocrine unit familiar with the complexity of patients’ needs is recommended. To achieve this, rehabilitation, reproductive, neuropsychological, and vocational services need developing further in parallel with appropriate transition processes to adult services if we are to better manage and improve outcomes for this high-risk group of young patients. Evidence- and consensus-based guidelines are increasingly being developed to define a standard of best practice for the management of these rare tumors.

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