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 »  Abstract
 »  Tumours and Thei...
 » Clinical Features
 »  Sequence of Loss...
 »  Sellar and Supra...
 »  Radiotherapy and...
 » Key Points
 »  References
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REVIEW ARTICLE
Year : 2020  |  Volume : 68  |  Issue : 7  |  Page : 28-32

Endocrinological Management of Sellar and Supra-Sellar Tumors in Children


1 Senior Pediatric & Adolescent Endocrinologist, Jehangir Hospital, Pune & Bombay Hospital, Mumbai; Department of Health Sciences, Pune University, Pune, India
2 Clinical and Research Fellow, Pediatric Endocrinology, Jehangir Hospital, Pune, Maharashtra, India

Date of Web Publication24-Jun-2020

Correspondence Address:
Dr. Vaman Khadilkar
Jehangir Hospital, Pune and Bombay Hospital, Mumbai, Maharashtra
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0028-3886.287676

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 » Abstract 


CNS tumours and their treatment commonly lead to endocrinopathies in children. Advances in surgical techniques, chemotherapy and radiotherapy have improved the survival in children with CNS tumours however they have also added to the late effect burden. Since the pituitary and hypothalamus regulate many important bodily functions, loss in their function leads to major derangements in growth and hormonal milieu. This article is a review of clinical presentation, diagnosis and management of endocrinopathies encountered in common sellar and supra-sellar CNS tumours in children. The management is divided into mainly two sections: immediate (peri and post-operative) and long term.


Keywords: CNS tumours, children, endocrine management
Key Message: Endocrine dysfunction should be anticipated and monitored in children with CNS tumours. Hormonal disturbances can be caused primarily by the tumour or because of its treatment. Evaluation of both, pituitary hypofunction and hyperfunction is indicated. In addition to the neurological signs and symptoms, CNS tumors in children can manifest as growth disorders or endocrinopathies before the neurological signs and symptoms. Endocrinological management is needed in the peri operative period as well as for the later effects of therapy.


How to cite this article:
Khadilkar V, Karguppikar M. Endocrinological Management of Sellar and Supra-Sellar Tumors in Children. Neurol India 2020;68, Suppl S1:28-32

How to cite this URL:
Khadilkar V, Karguppikar M. Endocrinological Management of Sellar and Supra-Sellar Tumors in Children. Neurol India [serial online] 2020 [cited 2020 Jul 15];68, Suppl S1:28-32. Available from: http://www.neurologyindia.com/text.asp?2020/68/7/28/287676




Important bodily functions of growth, development, reproduction and homeostasis are controlled by the pituitary gland in conjunction with the hypothalamus. Partial or complete loss of anterior and posterior pituitary gland function is termed as hypopituitarism. Etiology for which range from conditions causing reduction in function or complete damage to the pituitary gland or due to improper hypothalamic secretion of pituitary releasing hormones.

With improved surgical techniques and the advent of chemotherapy and radiotherapy leading to better survival of children with CNS tumours, there is increase in the incidence of acquired hypopituitarism and other endocrinopathies.[1] Hypopituitarism may be broadly classified as primary (primary disorders of the pituitary gland) and secondary (involving the hypothalamus or pituitary stalk).


 » Tumours and Their Treatment Causing Hypopituitarism Top


CNS tumors (sellar and supra-sellar)

Craniopharyngiomas

Pituitary adenomas

Medulloblastomas

Gliomas

Germinomas

Ependymomas

Meningiomas

Chordomas

Cysts (Rathke's cleft cyst, dermoid cyst, arachnoid cyst).

Iatrogenic

Post neurosurgery

Post radiotherapy

Post systemic chemotherapy.


 » Clinical Features Top


Acquired hypopituitarism, usually caused by tumours, trauma or infections, may occur at any age and needs careful evaluation. For clinical manifestations to become apparent, at least 75% of the pituitary should be damaged.[2] The presentation may range from acute and life-threatening conditions like traumatic brain injury, CNS infections, pituitary apoplexy, hypophysitis to ill-defined slowly progressive loss of pituitary function. The condition may present with hormonal deficiencies (Growth Hormone, Follicle Stimulating Hormone, Luteinizing Hormone, Thyroid Stimulating Hormone and/or Adrenocorticotropic Hormone) or with features of the underlying disease like bony lesions (LCH); visual field defects like bitemporal hemianopsia, vomiting and headache (ICSOL).

Both growth failure due to growth hormone deficiency and excess growth due to growth hormone hyper-secretion are known to occur, the former being more common.[3] Early and late puberty may both be a clinical presentation of CNS tumours or its treatment. Craniopharyngioma presents with the clinical triad of growth failure, raised intracranial pressure (ICP) and vision loss. Other known endocrine manifestations of craniopharyngioma are growth failure, obesity, lack of sexual development and diabetes insipidus.


 » Sequence of Loss of Endocrine Function in CNS Tumours Top


The sequence of loss of endocrine function in tumours involving the hypothalamic, pituitary region is typical. First to be lost is the growth hormone followed by gonadotropins, ACTH and finally, TSH. GH deficiency in children is more obvious in children owing to growth failure and rarely, hypoglycemia. The loss of gonadotropin secretion may go unnoticed until puberty. Isolated ACTH insufficiency is not common. Diabetes insipidus may be the first clinical manifestation in Langerhans cell histiocytosis and other ICSOLs before other symptoms evolve. These patients require regular monitoring for early detection of loss of other endocrine function.


 » Sellar and Suprasellar CNS Tumours Top


Craniopharyngioma is the most common CNS tumour encountered in the pediatric age-group. Hypotahlamic hamartomas causing precocious puberty are also common. These are discussed in detail, other tumours like prolactinoma, medulloblastoma, germinoma, and pituitary adenoma are discussed briefly. Treatment of these tumours, in the form of cranial irradiation and chemotherapy, also cause endocrine pathology.

Craniopharyngioma (CP)

Craniopharyngiomas (CPs) are embryonic malformations of the sellar and parasellar area. First described by Zenker in 1857, the first attempt at surgical removal was by Lewis in 1910. Susman detected squamous epithelial cells in the pituitary gland in pediatric population. The term 'craniopharyngioma' was coined by Cushing in 1932. CP represents 1.2 to 4% of all childhood intracranial tumors. 30 to 50% of all cases of CP present during childhood and adolescence.[4] Though CP can be detected at any age, a bimodal age distribution is seen with first peak between 5 to 14 years and second between 50-74 years with equal gender distribution.[5] They can be either Adamantinomatous (more common in children) or papillary. Mutations in exon 3 of CTNNB1 have been associated with adamantinomatous type and BRAF mutations have been identified in the papillary variant.[6]

Most of the CPs occur in the sellar/parasellar region. 53-75% of CPs have a supra and intrasellar component while 20-41% of CPs are purely suprasellar; intrasellar are the rarest accounting for 5-6%.[7] Owing to their location, the tumours may present with pressure effects on the visual pathways, brain parenchyma, blood vessels and the HP axis. The symptoms may evolve over weeks to occasionally years. Presentation varies according to age. Increased ICP, visual field defects, papilledema and cranial nerve palsies are more common in younger age groups while adolescents present frequently with growth failure, delayed puberty, obesity and less frequently with precocious puberty and syndrome of inappropriate Anti diuretic hormone (SIADH).

About 40-87% of patients present with at least one hormonal deficit at the time of diagnosis. Endocrine deficits most seen are GH (26-75%) followed by gonadotropins (40%), ACTH (25%) and TSH (25%).[8] Diabetes insipidus (DI) presents preoperatively in 17 to 27% cases. Post-surgically, it is seen transiently in 80-100% cases and becomes permanent in 40-93%. After treatment, the hormone deficiencies encountered are GH (70-92%), gonadotropins (80-95%), ACTH (35-88%) and TSH (39-95%).[9] Pathologically reduced growth rate—an early manifestation of the disease—occurs in patients as young as one year, but significant weight gain, predictive of hypothalamic obesity, tends to present later, shortly before diagnosis.[10]

Obesity is seen in 12-19% patients at the time of diagnosis and severe obesity in up to 55% after treatment. This predisposes the patients to cardiovascular disease and metabolic syndrome. Though the mechanisms leading to obesity are not completely understood, vagally mediated hyperinsulinemia and endogenous leptin insensitivity have been hypothesized.[10] For the detection of CP, MRI with gadolinium is the standard investigation. Calcifications are better picked on computerized tomography. Tumors of 2-4 cms are common and up to 12 cms have been reported.

Hypothalamic hamartoma (HH)

Hypothalamic Hamartomas are congenital malformations located in the ventral hypothalamus. These usually present with the classic triad of gelastic or 'laughing' seizures, central precocious puberty (CPP) and cognitive impairment. Genetic mutations in GLI3 gene have been implicated.[11] It is postulated that the CPP happens because of ectopic pulsatile release of gonadotropin releasing hormone (GnRH). Clinical symptoms of HH strongly depend on its attachment to the hypothalamus. Those attaching to anterior pituitary and pituitary stalk are more closely associated with precocity. Mean age of first sign of puberty is 3.7 years in males and 2.5 years in females.[12] If left untreated, these children progress to develop secondary sexual characteristics, and though the height is abnormally advanced at the presentation, they end up shorter than their genetic potential due to premature fusion of the epiphyses. Diagnostic evaluation includes MRI brain, USG pelvis and hormonal assay including FSH, LH, estradiol/testosterone. In certain cases of precocious puberty, a GnRH stimulation test may be performed to confirm the diagnosis to test the magnitude of LH rise in response to GnRH. Treatment with 1-3 monthly depot preparations of GnRH agonist according to the weight of the child is effective in stopping the progress of puberty though manifestations of adrenarche, such as axillary and pubic hair development, may progress. Menarche occurs 9-18 months after discontinuation of therapy and fertility remains intact.[12] Surgical management is often required for patients with intractable seizures and sessile tumours. Diabetes insipidus may be encountered as a transient complication after surgery. Pituitary function should be evaluated after the surgery as multiple pituitary hormone deficiencies and hypothalamic obesity syndrome may ensue.

Other CNS tumours

Germinoma

Germinomas are the most common germ cell tumors, CNS germinomas account for 3-5% of pediatric brain tumours. There is a slight male preponderance (M:F 1.88:1); 49% are suprasellar and 37% pineal, arising in the midline locations.[13] There are reports of increased incidence of germinomas in Down syndrome, Klinefelter syndrome and Noonan syndrome.[14]KIT/RAS pathway mutations are the most common mutations reported in germinomas.[15] Usual presentation of pineal tumours is symptoms of raised intracranial pressure, visual abnormalities and Parinaud syndrome (nystagmus, upward gaze palsy, pupillary light-near dissociation). Endocrine manifestations are more common with suprasellar tumors, most common being DI followed by growth failure and delayed puberty. Treatment includes surgery, radiotherapy and chemotherapy depending on extent and location of the tumour.

Pituitary adenoma (PA)

Although it is the most common pituitary disease seen in adults, it is rare in children and accounts for <3% of supra-tentorial tumors in pediatric population.[16] These are usually benign and the symptoms are due to endocrine hyperfunction or owing to intracranial pressure changes. Adenomas may be found to secrete ACTH, prolactin, GH, and rarely TSH.

Prolactinoma

Presentation of prolactinomas vary from headache, visual disturbance, gynecomastia, galactorrhea, delayed puberty, oligo-amenorrhea, and rarely growth failure. Prolactin level of >200 ng/l are diagnostic (pooled sera are preferred as single measurement is not reliable). Mutations of genes such as GNAS, PRKAR1A, MEN1 and AIP have been implicated in PA.[17] First line management of prolactinomas is cabergoline or bromocriptine. Cabergoline is better tolerated and convenient as frequency of dosages is less. For all other PAs, and refractory prolactinomas, trans-sphenoidal surgery is the first line management. In cases where surgery is contraindicated, non-secreting adenomas or failure of suppression of hormones even after surgery, radiotherapy is used.

Rathke's cleft cyst

These are rare, benign cysts originating from the embryological remnants of Rathke's pouch and usually discovered incidentally on imaging. They present with headache, visual deficits and hormonal disturbance (commonest being Growth hormone deficiency and hyperprolactinemia followed by hypocortisolemia, hypothyroidism and diabetes insipidus). Small (<10 mm) and asymptomatic RCCs may be monitored using MRI for increase in size, appearance of symptoms while the larger ones need surgical excision.[18]

Medulloblastoma (MB)

Of the malignant intracranial tumours in children, MB is the commonest. 70% cases occur in the first decade. It is more commonly seen in males (M:F ratio 2:1).[19] MBs are typically known to occur in the midline of the posterior fossa. These arise from the medullary velum and occupy the fourth ventricle and spread to the brain and spine via the CSF. MBs are rapidly growing tumours and are best visualized on MRI. Surgical excision followed by radiotherapy and adjuvant chemotherapy is the treatment of choice. Low dose radiation (<30 Gy) leads to isolated growth hormone deficiency in 30% cases, while with higher doses (30-50 Gy) endocrine deficiencies encountered are GH in 50-100%, gonadotropin in 20-30%, TSH in 3-9%, and ACTH in 3-6%.[20] With cranio-spinal irradiation primary hypothyroidism can also occur.

Pre-operative endocrine workup in Pediatric CNS tumours

Work-up before surgery includes visual field testing, neurological evaluation, MRI brain and spine and testing of pituitary function. When hyperfunctioning pituitary is suspected (prolactinoma, acromegaly, Cushing disease) measurement of serum prolactin, IGF-1, GH and cortisol is useful. In GH secreting tumours GH suppression test with oral glucose administration is performed to confirm the diagnosis. In case of suspected hypo functioning pituitary (hypothyroidism, hypogonadism and adrenal insufficiency), free T4, free T3, FSH/LH, testosterone, estradiol, morning serum cortisol and Synacthen (ACTH stimulation) test are performed.

Since cortisol has a permissive role in tubular excretion of water, DI may be occult and will present only after the cortisol replacement. Serum electrolytes, urine specific gravity and detailed history may throw light on possible DI. Though it is ideal to correct for DI, hypothyroidism and adrenal insufficiency before undertaking surgery, it would be inappropriate to delay surgery for the same. In patients in whom it is not possible to assess endocrine function before surgery, it is prudent to give injection hydrocortisone in a dose of 100 mg/sq. meter at the induction of anesthesia to avoid adrenal crisis. The replacement of GH and sex hormones is deferred until after the surgery.

Peri and post operative endocrine workup and management of CNS tumours

The management is described under two headings: early post-operative period and long term follow up.

Early post-op management

Fluid, electrolyte imbalance and adrenal insufficiency (AI) are commonly observed. Water metabolism may be affected by the initial release ADH due to handling during surgery, followed by central DI due to ADH deficiency. Rarely this is complicated by cerebral salt wasting (CSWS). Central DI may be partial or complete, transient or permanent, depending on the extent of damage to the neurons of the hypothalamus. It is usually transient but may become permanent. Younger patients, males and patients with very large intrasellar masses are at a higher risk of developing permanent DI. Polyuria is usually abrupt, occurring within the 12–24 hours after surgery.[21] During the first 12-24 hours after surgery, polyuria occurs, which in a stable patient with intact thirst does not require any intervention as it is compensated for with increased water drinking. In some children, a few doses of DDAVP are sufficient till the condition resolves.

In about 3% of the patients, a triphasic pattern is seen: polyuric phase followed by antidiuretic phase, and finally a polyuric phase, which is usually chronic [Figure 1]. Hyponatremia peaks around 5-8 days after surgery and may be heightened by concomitant hypercortisolism. Sodium level between 130-135 mmol/L can be managed with fluid restriction but, symptomatic hyponatremia with sodium level <125 mmol/L8 needs restriction of fluids with administration of hypertonic saline or vaptans.[22] In cases where AI is diagnosed before surgery, 50-100 mg/m2 of hydrocortisone or 2-4 mg of dexamethasone is indicated at the time and immediately after surgery. The dose is then gradually reduced to return to 10-12 mg/m2/day of hydrocortisone over the next 48-72 hours. The chances of Hypothalamo-Pituitary Adrenal Axis (HPAA) recovery in such cases after pituitary surgery are very low. The patient is highly likely to need a lifelong steroid replacement therapy. A morning serum cortisol is sufficient to make a diagnosis of persistent AI. It is important to exclude AI before starting the patient on levothyroxine or growth hormone to prevent adrenal crisis. Treating AI may unmask central DI and precautions should be taken to prevent it.
Figure 1: Water metabolism showing triphasic response after pituitary surgery

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Late post-op management

A repeat assessment of pituitary function is recommended 6 weeks after surgery. Sometimes pituitary hormone deficiencies can recover postoperatively and will be detected as part of this evaluation. Hydrocortisone should be withheld 3 days before the testing and should be replaced with dexamethasone (since dexamethasone does not affect the cortisol assay). Lifelong treatment is usually required in patients who are found to be cortisol deficient. Stress dose of cortisol is explained to the patient where the dose of Hydrocortisone is doubled or tripled during illness for 2-5 days. Free T3 and T4 are used for evaluation of thyroid function since TSH is of value only in cases where the pituitary is intact. Replacement dose is started at 100 ug/m2/day or 1.6 ug/kg/day. In cases with absence of secondary sexual characteristics or with low testosterone, estradiol, FSH and/or LH, replacement for gonadal insufficiency is started when the age of puberty is reached. Ethinyl estradiol is started at 2 ug/day and is increased to 20 ug/day, at which point, progesterone is added. Testosterone is started at 25 mg/month and is gradually increased to 250 mg/month. HCG/HMG may be considered later for induction of fertility. Growth is monitored and GH therapy is contemplated depending on the growth pattern though, it is deferred for 1-2 years after completion of surgery, radio or chemotherapy. Subsequently, patients are followed up on a 6-12 monthly basis for evaluation of pituitary function.[23]


 » Radiotherapy and Chemotherapy Induced Hypopituitarism Top


HPA tumours, non-pituitary brain tumours and nasopharyngeal tumours are treated with cranial irradiation and this leads to iatrogenic panhypopituitarism. Radiotherapy is known to cause damage to the hypothalamus and the pituitary. Radiotherapy schedule, dose and the fraction size determine the time of onset and the extent of hypopituitarism.[24] GH deficiency is more common after the low-dose radiation (18-24 Gy) whereas, doses larger than 30 Gy result in multiple pituitary hormone deficiency [Table 1]. Pre-pubertal children are more susceptible to damage than post-pubertal children. Also, chemotherapy has an additive effect on the radiation induced damage to the pituitary function and a single large fraction of radiotherapy is more damaging than multiple smaller fractions.[25] The commonest function affected is that of the GH (14-93%), followed by gonadotropins (14-34%). Since the HP adrenal and thyroid axes are more resistant to damage caused by radiation, ACTH and TSH are less commonly affected.[26] Both precocious and delayed puberty have been reported post irradiation.[27] Though there are reports of chemotherapy causing HPA dysfunction, the effects are subtle.
Table 1: Endocrine effects of Cranial irradiation on Hypothalamo-pituitary axis in children

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 » Key Points Top


  • Pituitary hormone dysfunction may be caused by primary (pituitary conditions) or secondary causes (hypothalamic conditions)
  • Growth failure, diabetes insipidus and other anterior pituitary hormone dysfunction are indicators of hormonal disturbance in children with intracranial space occupying lesion. High index of suspicion and timely monitoring is required to make a diagnosis of endocrine disturbance
  • Increased intracranial pressure (ICP), vision loss and growth failure form the classic triad of craniopharyngioma which is the commonest childhood tumour
  • Molecular genetic testing helps in guiding diagnosis, treatment and prognosis. Hence, is recommended in children with CNS tumours
  • Endocrine disturbances may be evident months or years before other symptoms of CNS tumours become apparent
  • Evaluation for both pituitary hypofunction (GHD, hypogonadism, adrenal insufficiency and hypothyroidism) and hyperfunction (Cushing disease, acromegaly, prolactinoma) is indicated in all children with CNS tumours
  • Post-operative endocrine management of CNS tumors is divided into early (disorders of water, electrolyte balance and adrenal insufficiency) and late (evaluation and treatment of other hormone deficiencies)
  • Growth hormone is the commonest affected hormone followed by gonadotropins, FSH and LH post-radiation
  • Chemotherapy may lead to hormonal disturbances but they are milder than those caused by radiotherapy.


Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
 » References Top

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