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First described by Saxer in 1902 and subsequently named by Cushing in 1932 craniopharyngiomas are slow growing non-glial tumours arising from remnants of the craniopharyngeal duct and/or Rathke's pouch. They are epithelial-squamous tumours with a variable cystic component which occupy the sellar region of the brain  4. The exact pathogenesis remains to be clarified, however 2 theories of note have been proposed; transformation of squamous cell rests in the embryonic craniopharyngeal duct, and metaplasia of anterior pituitary cells (gland/stalk) giving rise to craniopharyngiomas4  6.
Although rare and accounting for only 2-5% of all primary intracranial tumours, they are notable for their prevalence in children in whom they represent as many as 15% of primary brain tumours  . While possibly the most common tumours to arise from the pituitary region in children, the absolute incidence remains at 0.13 cases per 100,000 per year with a bimodal distribution demonstrating a peak childhood incidence in the 5-14 age group (childhood tumours represent up to 50% of all craniopharyngiomas  ) and a peak in adults between ages 65-74  . Such a distribution may result from different pathophysiological mechanisms in adults and children4, with the histological papillary (solid) subtype primarily occurring in adults whilst the adamantinomatous subtype (solid and cystic component) affects mainly the young.
MRI image demonstrating large calcified mass in suprasellar space (arrow). From: http://emedicine.medscape.com/article/339424-overview Craniopharyngiomas have been histologically categorised by the World Health Organisation as benign stage 1 tumours though they are often described as having malignant behaviour4. The consequences of having a mass of only a few centimetres diameter within the brain can be debilitating. Although they may arise anywhere along the craniopharyngeal duct, they tend to be located in the sellar/parasellar region of the brain. The location of the neoplasm in close proximity to the optic chiasm and/or optic nerves can result in visual impairment and local effects on pituitary and hypothalamic function can result in a plethora of symptoms due to hormone dysregulation. As with other cerebral neoplasms, raised intracranial pressure often follows from the effects of an increased mass within the sealed box which is the skull and potentially leads to headache and papilloedema. A 2005 study on 121 craniopharyngioma cases by Karavitaki et al found that headache and visual field defects were the 2 most common presenting symptoms  .
Craniopharyngiomas do not tend to present until the mass has grown sufficiently such that it can impinge on adjacent cerebral structures and cause symptoms. This may be several years after the disease process has begun and the tumour may have become several centimetres in diameter upon identification. A diagnosis of craniopharyngioma is suggested by clinical features and may be confirmed using imaging studies. The presence of a craniopharyngioma is strongly suggested by the appearance of a suprasellar calcified cyst on CT scan which is an excellent imaging tool for diagnosis. Contrast may be used to enhance solid tumour components and may reveal both solid and cystic elements. MRI scans are necessary to pinpoint the exact location of the tumour and are used to reveal its precise composition and surrounding structures. This is of paramount importance in planning an efficacious treatment plan and may influence surgical management based on location and invasion.
The optimal management of craniopharyngiomas varies based on size, histology and tumour location. These variables often impact on survival, limitation to performance of daily activities, quality of life as well as frequency and severity of symptoms. Current management aims to improve long-term survival whilst maintaining the quality of life and often involves the implementation of several therapeutic modalities  . As with many cancers, management options include surgery, radiotherapy and chemotherapy, both individually and as combination therapies. A treatment algorithm has recently been proposed by Karavitaki et al based on the literature regarding the outcome of treatment for this rare tumour  and may be used as a reference to indicate which cases are amenable to different therapeutic strategies.
The natural progression of untreated craniopharyngiomas is unclear and is likely to remain this way due to ethical problems regarding withholding treatment. It is assumed that early intervention is the best option given the continual tumour growth following initial identification which translates into increased symptoms and a reduction in quality of life for the patient. Karavitaki et al found that 92% patients who were not immediately operated on demonstrated further tumour progression (indicated by their histories) and as a result progressed to requiring surgery  .
Current guidelines advise surgery as first-line treatment for symptomatic craniopharyngiomas. These tumours provide the neurosurgeon with a very challenging removal operation and for this reason Harvey Cushing identified them as a 'baffling problem to neurosurgeons'  . Proximity to vital structures combined with unclear tortuous borders and adherence to important neurovasculature renders complete excision difficult and enhances the likelihood of complications resulting from damage to vital brain areas. For this reason, the performance of gross total resection rather than partial resection has been the subject of much debate. A 1999 study by Fahlbusch et al on 168 patients found that 0% of tumours more than 4cm in diameter could be completely excised due to extension into vital brain areas. Retrochiasmic/3rd ventricular location, high degrees of calcification, invasion into surrounding brain regions and the presence of hydrocephalus were also found to enhance surgical difficulties regarding resection shown as a negative correlation with the extent of surgical resection  . The authors reported that the main reasons for an incomplete resection were hypothalamic and vascular involvement of the tumour.
Although the less traumatic trans-sphenoidal approach for surgical removal is a potential option, this approach is only of use for small intrasellar tumours and is not applicable to the majority of cases which require craniotomy through one of several possible approaches (trans-cortical, bi-frontal, sub-frontal, frontopterional the list goes on)  1718. The approach varies based on location and the preference/experience of the individual surgeon, however tumours arising in children usually extend to the supra-sellar area and as a result require utilisation of the transcranial route  . Some tumours call for the use of combined approaches which often entails attacking the tumour from above and below via a transcallosal/transventricular approach with a basal craniotomy (respectively). In a study on 142 patients Yasargil et al found that the two combined approaches can feasibly be performed during the same operation  . Controversy surrounds the subject of total gross resection in unfavourably located tumours in children. Tumour recurrence despite what appears a complete resection is problematic, and negative effects on hypothalamic function (along with other iatrogenic deficits) have been observed following attempted gross total resection  .
Although whether or not to perform partial or radical resections is a cause for debate, it is generally agreed that radical excision should be aimed for so long as important brain structures will be unharmed. Radical removal is often accompanied with more operative complications  but bears a chance of complete cure. Partial resection appears tempting considering the lower peri-operative morbidity and promising initial results, yet it is often followed by tumour progression and ultimately a worse prognosis  . However, Karavitaki et al found that the rates of peri-operative mortality were not significantly greater in gross total resection than partial resection, and ranged from 1-8%, identifying that this may indicate 'hazardous manipulations' of vital brain regions occurs regardless of the degree of excision  . Interestingly they performed radical surgery on just 18% of their patients. This is in contrast with other studies in which a much larger proportion of patients underwent gross total resection (demonstrated using post-operative imaging). A study on 56 patients by Weiner et al demonstrated 77% of childhood cases were successfully treated by radical resection  and likewise, a study on 122 patients by Van Effenterre et al demonstrated 59% underwent total resection  . Total tumour removal rates of as high as 85.7%  have been reported using certain surgical approaches. Reasons for such disparity in the degree of surgical resection are unclear. It may be entirely a result of anatomical variables with regard to tumour location, though it is likely that judgement and experience of individual surgeons has a role, with some opting for a more aggressive approach whilst others prefer a more conservative partial removal followed by radiotherapy.
In tumours with a large cystic component causing pressure on local structures, aspiration may be necessary prior to surgery. This is a means of providing symptomatic relief by removing the fluid component of the tumour, leaving only the solid component to be identified and removed by the surgeon. It is important to note that fluid aspiration is not a means of delaying definitive treatment. In a 2005 study on 121 craniopharyngioma cases, Karavitaki et al found that 81% of patients requiring cystic fluid aspiration experienced reaccumulation of fluid within 36 months  . Gutin et al demonstrated that grossly cystic craniopharyngiomas which recur following surgery may be treated with intermittent aspirations using an Ommaya reservoir drainage system  ; effectively a catheter sitting inside the tumour from which the cystic fluid can be aspirated. This indicates a role for cystic drainage in symptomatic management of cases refractory to surgical intervention.
Surgical mortality rates have greatly improved over the decades, owing in large part to improvements in surgical technique, imaging and post-operative hormonal therapy to correct iatrogenic endocrine deficits. The current peri-operative mortality stands between 1.7% and 5.4%  . A 1990 study by Yasargil et al reported a mortality rate of 16.7%, however this is probably not representative of current surgical intervention and is most likely related to the aggressive approach of total resection employed on all patients in the study  . Even this considerable peri-operative mortality is dwarfed by rates as high as 41% when craniopharyngioma surgery, along with medical imaging was in its relative infancy  3334.
Until the 1930s, craniopharyngiomas were not thought to be responsive to radiotherapy. Carpenter et al conducted a study in which cystic craniopharyngiomas were aspirated and then subjected to high doses of radiation  . Although the results were positive, the study had just 4 subjects and consequently lacked statistical power. It was not until the 1960s that radiotherapy became a mainstream therapy for craniopharyngiomas. This was after the publication of a 1961 study by Kramer et al in which radiotherapy was successfully implemented to treat craniopharyngiomas following Burr-hole aspiration of cystic tumours  . Current guidelines advocate the use of fractionated external beam radiation in cases of partial surgical resection (with residual tumour tissue in post-operative imaging) and cases of small tumours not producing compressive symptoms following a biopsy diagnosis  .
Tumour recurrence rates are very high following partial surgical resection  and a recent review of the literature put the recurrence rate at 25-100% (gross total resection is associated with a smaller risk of recurrence)  . Recurrence is associated with significant morbidity and mortality resulting from locally aggressive behaviour and proximity to vital structures. Fractionated external beam irradiation significantly reduces recurrence rates  41and in recent decades there has been something of a shift towards less aggressive surgery given the considerable morbidity and mortality associated with radical surgery. This effectively means a subtotal resection followed by radiotherapy is deemed sufficient to control the tumour whilst limiting recurrence. A literature review by Yang et al investigated the outcomes of 442 cases following several different treatment methods since 1990. Interestingly the study showed that although gross total resection was associated with significantly improved tumour control (evidenced radiographically) and overall survival when compared to partial tumour resection, these differences disappeared when partial resection was followed by radiotherapy. The authors concluded that sub-total resection followed by fractionated external beam radiation is a reasonable approach for tumour control whilst limiting hypothalamic damage and pituitary dysfunction; common sequelae of radical surgery.
However, radiotherapy is not without its problems. Cystic tumour enlargement can result from radiotherapy in a significant proportion of patients, causing acute deterioration. Although this has been shown to often regress spontaneously  , symptoms can be very serious and include visual defects (from local pressure effects), hydrocephalus (owing to inflammation of ventricular epithelial lining  ) and potentially even global deficits and loss of consciousness. This radiotherapy induced deterioration can result in death unless appropriate surgical intervention is implemented  . Further caution must be taken when using radiotherapy on children as they tend to be vulnerable to treatment failure and side effects such as endocrine deficiencies, vascular damage, cognitive defects and secondary tumours resulting from high dose irradiation  . However, the development of better imaging modalities and conformal radiotherapy have allowed more precise targeting of the tumour, enabling lower doses to be used without significantly affecting tumour control  . This means less radiation administered to brain parenchyma and a reduction in side effects. In spite of these advances, children (in whom the brain is still developing) remain susceptible to adverse effects of radiotherapy and this must be taken into account when planning their treatment. This involves balancing the impact of a space occupying lesion and potential damage from future surgeries with radiotherapy induced cerebral damage to attain the best possible outcome for each individual.
Morbidity and mortality following treatment
Although much morbidity results from primary tumour invasion and recurrence, a variety of post-operative/radiotherapy complications are encountered resulting from damage to vital brain structures. These can present in many ways, but endocrine, visual, hypothalamic and cognitive problems are amongst the most frequently encountered and can be debilitating  48.
Hypopituitarism is reported in a significant number of patients, involving deficits in growth hormone, follicle stimulating hormone and thyroid stimulating hormone, with more than 50% of patients experiencing deficits of 3 hormones or more  . These deficits can largely be corrected medically, and a 1998 study by price et al demonstrated excellent growth in children treated with growth hormone following craniopharyngioma induced deficits. 79% reached heights over -2SD of their targets and many showed evidence of further potential to grow  . Interestingly, Geffner reported accelerated growth following surgical resection of craniopharyngiomas in children left unable to produce growth hormone who remained untreated. Although the mechanism of this phenomenon remains to be elucidated, this observation has led the way to further research  .
Although visual field defects are a common presenting feature of craniopharyngiomas (classically a bitemporal hemianopia resulting from compression of the optic chiasm), they may be a result of surgical intervention and radiotherapy which can lead to visual deterioration. Duff et al found in a 2000 study on 121 patients that following surgical tumour removal, 23.5% reported worse left eye visual acuity and 24.3% reported worse right eye acuity. 62.5% patients reported at least a quadrantinopia visual field defect during the 10 year follow-up and 26.1% of patients not presenting with visual problems experienced deterioration during treatment  . Similarly, a 2005 study by Karavitaki et al found 48% patients reported at least a quadrantinopia at 10 years follow-up (this increased to 72% at 20 years)  .
Hypothalamic circuitry is important in the regulation of appetite and satiety. Damage caused by tumour invasion, surgery or radiotherapy most commonly presents as obesity and hyperphagia. Loss of temperature control can also occur, as can cognitive impairment and sleep disturbance  55. Hypothalamic tumour invasion, young age of presentation, high radiation dose and hypothalamic symptoms at diagnosis are all predictors of hypothalamic morbidity  . Hyperphagia and increased appetite result in weight gain which is enhanced by inability to exercise due to visual, cognitive and neurological disturbances, combined with daytime somnolence due to sleep disturbance. Exercise and diet control must be implemented to avoid catastrophic obesity related complications.
When combined with the cognitive and neuropsychological deficits related to craniopharyngiomas, the plethora of morbidity linked with this particular tumour serve to worsen the functional outcome and adversely affect independent living and social integration with significant impact on occupational and educational status  58.
Studies have demonstrated significantly increased mortality rates following treatment for craniopharyngiomas compared with the general population. In a 2001 study into the impact on hypopituitarism on survival, Tomlinson et al demonstrated a significantly increased incidence of cardiovascular, cerebrovascular and respiratory mortality rates in patients with an underlying craniopharyngioma diagnosis, which was found to be the biggest independent risk factor for premature mortality in patients with hypopituitarism  . A 1998 study by Bulow et al demonstrated a five-fold increase in mortality in patients operated on for craniopharyngioma when compared with the general population  . This resulted from enhanced cardiovascular and cerebrovascular mortality. This suggests that even following successful tumour removal, survival remains adversely affected. The data for this study was collected between 1951 and 1988 and as a result must be interpreted cautiously as craniopharyngioma management has advanced dramatically in the past 50 years, potentially rendering older data less reliable. DeVile et al have suggested that endocrine deficiencies may underpin the increased mortality in children with previous craniopharyngiomas  . Hypoglycaemia and hypoadrenal crises due to loss of adrenal function, and reduced/absent thirst due to antidiuretic hormone deficiency are likely contributing factors.
Current guidelines recommend initial treatment of craniopharyngiomas (which cause compressive symptoms) should involve surgical resection followed by adjuvant external beam irradiation. Partial resection debulks the tumour, reducing pressure effects on local structures (such as visual pathways) whilst preserving surrounding brain parenchyma in the hope that radiotherapy can destroy any remaining tumour tissue identified on brain imaging whilst preventing relapse. Should the tumour recur following surgery and radiotherapy, other treatment modalities may be called upon bearing in mind the increased morbidity as well as mortality associated with repeat neurosurgery  . These may include stereotactic radiosurgery/radiotherapy, intracystic radiotherapy (brachytherapy), intracystic bleomycin and even systemic chemotherapy. Although not as commonly used or as widely studied (with adequate statistical power) as surgery and external beam radiotherapy, these strategies enable specialists to individualise treatment to a patient in whom standard modalities have failed or are not appropriate  .
Although considered low grade tumours by the World Health Organisation, craniopharyngiomas are associated with serious morbidity and mortality with an often unfavourable long-term outcome. The optimal treatment strategy is a subject of much controversy. This is not helped by the relative rareness of craniopharyngiomas and the paucity of large, prospective, randomised controlled trials with much of the current data being drawn from small, retrospective, non-randomised studies from which therapeutic outcomes are difficult to evaluate. Given the improvements in craniopharyngioma therapies over the past few decades which have been reflected in published morbidity and mortality data, surgery with adjuvant radiotherapy is likely to remain the mainstay of treatment until large studies demonstrate an alternative with a more encouraging outcome.