Childhood Craniopharyngioma

Dr Michele O’Connell 
Staff Specialist, Dept of Endocrinology, Royal Children’s Hospital, Melbourne.

Contents

Background

Craniopharyngiomas are tumors that arise from cells in the area of the brain close to the pituitary gland and its stalk. These tumours are classified as benign, in that they rarely spread to other parts of the body. Long-term survival rates are also very high (~90-95% 5-10 year survival). However because of their location and proximity to important nearby structures, both the tumour itself and its treatment can result in a number of long-term effects or ‘morbidities’ that can impact on well being and quality of life. This article aims to give an overview of the long-term problems that can result from craniopharyngioma.

How does a craniopharyngioma present?

Although present from birth, the first symptoms of a craniopharyngioma may appear at any time between childhood and old-age. Overall up to 50% present in childhood and adolescence where they account for ~10% of all paediatric brain tumours.

The first symptoms of a craniopharyngioma usually relate to effects of growth of the tumour on surrounding parts of the brain. By its nature and position, an enlarging craniopharyngioma can put pressure on nearby delicate structures which include the pituitary gland, the hypothalamus (and/or the connections between them), the optic nerves from the eyes and the fluid-filled spaces of the brain called the ventricles. Symptoms can therefore relate to:

  • ‘Mass effect’ due to increased size of the tumour and build-up of pressure within the skull; this most commonly results in headache (with or without nausea and vomiting)
  • Visual disturbance as result of pressure on the optic nerves; this is present in ~50-80% of all children but may go unnoticed in the early stages
  • Endocrine problems / effects on hormonal secretion – discussed in more detail below
  • Other symptoms such as tiredness, disturbance of sleep patterns, change in weight / appetite, behavioural problems or poor concentration


Treatment options

Because of its location, a number of potential long-term morbidities can result from treatment of craniopharyngioma. Since long term survival rates are high, increasing emphasis is now placed on minimising associated co-morbidities where possible, in order to maximise quality of life.  Surgical options include attempts at complete resection, or alternatively ‘debulking’ or partial resection procedures. By nature, these tumours are ‘sticky’, adhering closely to surrounding structures and so complete resection is often impossible; moreover, complete resection can result in more profound damage to delicate nearby structures such as the hypothalamus. A balance therefore needs to be struck between obtaining as maximal a resection as possible (to reduce the risk of recurrence) and minimising the likelihood of unwanted long-term effects.  As a result, partial resection with subsequent radiotherapy is increasingly used as a treatment modality, particularly when the hypothalamus itself is directly involved. This is because hypothalamic effects and obesity in particular are known to impact very negatively on quality of life; hypothalamic obesity also independently impacts on long term mortality risk (see below also). Radiotherapy itself can also have independent therapy-related effects, particularly on the young, developing brain.  As a result, its use is largely reserved for those over 5 years old, although with newer more targeted ways of delivering radiotherapy specifically to the tumour, this is being reassessed.

Endocrine problems / effects on hormone secretion

Most patients with craniopharyngioma (85–95%) suffer from multiple deficits of hypothalamic–pituitary function. These deficiencies can result from effects of the growing tumour itself, or from its treatment with surgery and / or radiotherapy. Any or all of the hormones secreted by the anterior and posterior pituitary gland (see diagram) can be affected; commonly these deficiencies occur because the signals from the hypothalamus that control these pathways are disrupted. The evolution or timing of pituitary hormone deficiencies varies and they may be present at diagnosis, or arise in the years after treatment has been completed. Assessment of pituitary function at the time of diagnosis (prior to surgery if possible), in the initial months after treatment and on an ongoing basis is therefore very important. 


Once established, pituitary hormone deficiencies will persist and most require lifelong therapy. This will necessitate long term follow-up by an endocrinologist throughout childhood, adolescence and adulthood. Nonetheless, it should be remembered that all of the hormone deficiencies can be replaced using medications with good clinical and quality of life outcomes.

Pituitary hormone deficiencies - clinical impact and treatment options

1. Growth hormone (GH) deficiency
The majority of individuals (>80%) with craniopharyngioma will be growth hormone deficient, which means that the pituitary gland is unable to release growth hormone in sufficient amounts. In many this is present at the time of diagnosis; in others it results from either surgery or radiotherapy given as part of treatment. For the former group, poor or slower rates of growth may have been noticed in the years prior to diagnosis and children may be shorter than would be expected for their family; otherwise, slow growth may only arise in the early years after treatment.


Growth hormone (GH) replacement therapy can be given for those who are growth hormone deficient and growing slowly. In Australia, GH therapy is only available with government funding for children and adolescents who have yet to complete their linear growth / reach their final height. For children who are GH deficient because of a craniopharyngioma, GH therapy is generally deferred until the appearance of the tumour has been stable on serial brain scans for at least 12 months after the completion of therapy. GH replacement therapy has been shown to be safe and effective in this group of patients.
 

GH is given by injection into the fat tissue under the skin (usually on the thighs / abdomen or hip). There are various preparations available, all of which have similar effects on growth; the differences between products relate predominantly to the devices used to administer the dose. This can be discussed with your endocrinologist or endocrine nurse. The dose is given at night before bed (to mimic the higher levels secreted overnight by the pituitary gland).  In Australia, government funded GH replacement therapy continues until growth is >97% complete. This is assessed by a test called a ‘bone age’ which is an Xray of the wrist and hand which is used to assess the development of the growth plates of the bones.

At a bone age of 13.5years in girls and 15.5years in boys, adult height has almost been reached and GH therapy is discontinued. This does not mean that GH deficiency has resolved however and some adolescents and young adults will experience symptoms such as tiredness, poor energy, or an increase in the ratio between body fat & lean tissue without growth hormone. Unfortunately at present, the only option for replacement therapy is to fund the medication privately which is very expensive; the dose required as an adult is however, a fraction of that required during childhood and adolescent years of growth.

2. Gonadotrophin (LH and FSH) deficiency
Deficiency of these hormones results in a lack of stimulus to the gonads (ovaries or testes) to produce sex hormones (oestrogen in girls, testosterone in boys), which are needed to produce both the physical changes of puberty and ongoing sexual development. Replacement therapy is therefore not necessary in young children, but if no signs of puberty occur at the appropriate age (e.g. no breast development by age ~12y in girls or no increase in testicular volume by age ~14y in boys), then replacement therapy should be instigated. Ongoing therapy into and throughout adulthood is required.

In girls, oestrogen replacement can be given either by a daily tablet or a patch which is worn on the skin and changed weekly. Once oestrogen therapy has been established for ~2-2.5years, progesterone therapy is also added; and this results in menstruation. Progesterone can either be given as a separate tablet in a ‘cyclical’ fashion each month, or as a combined preparation such as is found in the oral contraceptive pill (OCP). If the latter is used, craniopharyngioma patients should be aware that during the week of ‘sugar’ or ‘placebo’ tablets that are part of each OCP pack, their ovaries will not be producing oestrogen (this is different to women who do not have a pituitary or ovarian problem but who use the OCP for contraception). As a result, it is preferable for those with gonadotrophin deficiency to skip the placebo tablets on approximately 2 of every 3 months (& start a new OCP pack directly). This will allow for more continuous oestrogen replacement which is very important for normal bone health.  This can be discussed with your endocrinologist.

In boys, testosterone can be given in a number of forms. The preparations most commonly used to induce puberty are either daily tablets or injections of testosterone every 2-4 weeks. Once adult levels of testosterone are reached, many men choose to switch to longer acting ‘depot’ testosterone injections or implants (which last ~12weeks); topical testosterone gels are an alternative form of therapy. 

It is important to know that although the signals that tell the gonads to produce sex hormones are affected by craniopharyngioma, the gonads themselves are not affected.  An individual’s inherent fertility should therefore not be affected and it should be possible to stimulate the gonads to either ovulate or produce sperm. This stimulation requires assistance with use of alternative hormone replacements (that mimic FSH and LH). This would be overseen by both your adult endocrinologist and/or a fertility specialist.

3. TSH deficiency
The thyroid gland which sits in the front of the neck plays an important role in both normal growth and development (especially brain development in the early years of life) and lifelong regulation of the body’s metabolism, through production of its hormone, thyroxine.  Thyroxine is produced by the thyroid gland in response to thyroid-stimulating hormone (TSH) production by the anterior pituitary. TSH deficiency means that the thyroid gland will no longer produce thyroxine. The resultant hypothyroidism may give rise to symptoms of lethargy, cold intolerance, constipation, dry skin and other symptoms of slowed metabolism. Treatment of hypothyroidism is relatively straightforward as thyroxine can be replaced in tablet form, taken daily.

4. Adrenocorticotrophic hormone (ACTH) deficiency
ACTH production by the anterior pituitary stimulates the adrenal gland to produce cortisol, a hormone that is vital for day to day wellbeing (blood pressure and blood glucose control) as well as ensuring the body’s normal response to stress or illness. Synthetic forms of cortisol replacement can be given in tablet form. In growing children and adolescents, hydrocortisone or cortisone acetate are used twice or three times daily; in older adolescents and adults longer-acting preparations such as prednisolone can also be used. 

The most important fact for individuals and families of someone with ACTH deficiency to remember is that in times of illness, the body cannot produce its normal ‘coping’ response of increased cortisol production. It is crucial therefore that extra hydrocortisone is given in this scenario. This may need to be by intramuscular injection – your doctor will discuss the dose with you. As cortisol deficiency during illness can be life-threatening, you should wear a medic-alert bracelet or carry information about your required medication requirements on your person at all times.

5. Anti-diuretic hormone (ADH) deficiency – Diabetes Insipidus
ADH is a hormone secreted by the posterior pituitary gland. It plays an important role in regulation of the body’s water balance by controlling excretion or retention of water at the kidneys. Deficiency of ADH is called diabetes insipidus – untreated, this results in the body being unable to appropriately retain water when necessary and hence an affected individual produces large quantities of very dilute urine. This may result in significant thirst, which is a protective adaptive response; however since the body’s thirst centre is in the hypothalamus, this may also be damaged after treatment for a craniopharyngioma. In this instance, a daily ‘water prescription’ may be required.  ADH can be replaced using synthetic preparations known the desmopressin or DDAVP. This is available in nasal spray, nasal solution or tablet forms. It is important not to give too much of this hormone, as excessive amounts cause excessive retention of water which can be dangerous for the body and brain. Your endocrinologist will monitor your response to your dosing schedule, but as a general ‘guide’ it is helpful to ensure that you have been passing increased amounts of urine in the hour or so prior to taking your next dose.

Direct hypothalamic effects / morbidities

In addition to controlling hormone secretion by the pituitary gland, the hypothalamus also plays a direct role in controlling many other behaviours including regulation of food and water intake, sleep, memory and temperature. There is increasing consensus that while pituitary effects of craniopharyngioma are ‘acceptable’, the hypothalamic effects are less-so.

While all hypothalamic functions are important, the loss of regulation of food intake (due to a loss of the signals of ‘satiety’ which tell a person when they are ‘full’ after a meal) can result in very significant weight gain, known as ‘hypothalamic obesity’. This has considerable knock-on health effects and also impacts very negatively on quality of life for the affected individual. Management is difficult, with food restriction and adequate daily exercise being the mainstays of therapy.  Recent novel therapeutic approaches for obesity following craniopharyngioma include combined diazoxide and metformin therapy (to combat high insulin levels) as well as gastric bypass surgery. To date these treatments are not routinely used in children and adolescents as their effects in adults are still being assessed.

Daytime sleepiness and memory disturbances can also have negative effects on quality of life, particularly as they impact on one’s ability to concentrate at school or work. Treatments such as melatonin, or occasionally amphetamine derivatives, may be useful and these can be discussed with your doctor. For children and adolescents, intermittent cognitive assessments with a neuropsychologist are an important part of long term follow-up after craniopharyngioma; specific modalities to circumvent or minimise the impact of any cognitive effects of treatment can therefore be put in place (e.g. advice to teachers regarding methods of delivering information to maximise its memory? retention etc).

As mentioned above, neurosurgeons are increasingly aware of the negative impact of these effects and so where possible, surgical procedures aim to avoid removal of tumour which is directly invading the hypothalamus.

Summary

Although technically classified as a ‘benign’ tumour, craniopharyngioma and its treatment can have a number of long term health effects on an individual. Multiple pituitary hormone replacement is very common, almost universal; however adequate hormone replacement of all deficiencies is possible and associated with good health outcomes.  Direct effects of the tumour or its removal on the hypothalamus are more difficult to manage and have more negative health and quality of life effects long-term.  Current treatment options therefore aim to minimise these effects, with the hope of improved outcomes and overall quality of life.

Updated:  March 2013