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Craniopharyngioma
Matthew R Garnett1, Stphanie Puget1, Jacques Grill2 and Christian SainteRose*1
Address: 1Department of Paediatric Neurosurgery, Necker Hospital for Sick Children, Paris, France and 2Department of Paediatric Oncology, Institute of Gustave Roussy, Villejuif, Paris, France Email: Matthew R Garnett - [email protected]; Stphanie Puget - [email protected]; Jacques Grill - [email protected]; Christian Sainte-Rose* - [email protected] * Corresponding author

Published: 10 April 2007 Orphanet Journal of Rare Diseases 2007, 2:18 doi:10.1186/1750-1172-2-18

Received: 7 December 2006 Accepted: 10 April 2007

This article is available from: http://www.OJRD.com/content/2/1/18 2007 Garnett et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract
Craniopharyngiomas are benign slow growing tumours that are located within the sellar and para sellar region of the central nervous system. The point prevalence of this tumour is approximately 2/100,000. The onset of symptoms is normally insidious with most patients at diagnosis having neurological (headaches, visual disturbances) and endocrine (growth retardation, delayed puberty) dysfunctions. Craniopharyngiomas are thought to arise from epithelial remnants of the craniopharyngeal duct or Rathke's pouch (adamantinomatous type) or from metaplasia of squamous epithelial cell rests that are remnants of the part of the stomadeum that contributed to the buccal mucosa (squamous papillary type). The neuroradiological diagnosis is mainly based on the three components of the tumour (cystic, solid and calcified) in the characteristic sellar/para sellar location. Definitive diagnosis is made following histological examination of a surgical specimen. The differential diagnosis includes other tumours in this region (pituitary adenoma), infectious or inflammatory processes (eosinophilic granuloma), vascular malformations (aneurysm) and congenital anomalies (Rathke's cleft cyst). The current treatment is gross total excision of the tumour, if there is no hypothalamic invasion or, in the presence of hypothalamic invasion, a subtotal resection with post-operative radiotherapy. Endocrine disturbances are normally permanent and need careful replacement. Overall, there is an 80% 5 year survival, though this can be associated with marked morbidity (hypothalamic dysfunction, altered neuropsychological profile).

Disease name
Craniopharyngioma

Definition and diagnostic criteria

The first description of a craniopharyngioma was in 1857 by Zenker. The term craniopharyngioma was introduced in 1932 by Cushing and has been used widely thereafter. In the International Classification of Diseases for Oncology 3rd revision (ICD-O-3) the code number 9350 refers to "unspecified craniopharyngioma", whilst 9351 and 9352 correspond to the two histological subtypes, adamantinous and papillary craniopharyngiomas, respectively.
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Synonyms
Rathke's pouch tumour, craniopharyngeal duct tumour, adamantinoma, adamantinomatous tumour, dysodontogenic epithelial tumour.

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The diagnosis of a patient with a craniopharyngioma is based on clinical (neurological and endocrine symptoms) and radiological (a calcified solid/cystic mass) findings, and is then confirmed by characteristic histological findings.

with the different histological subtypes, allows for two theories that may explain the origin of these tumours [6]:
The embryogenetic theory this suggests that the adamantinomatous type arises from epithelial remnants of the craniopharyngeal duct or Rathke's pouch. The duct and pouch were derived from the stomadeum, which, amongst other things, forms teeth primordia. The metaplastic theory this suggests that the squamous papillary type occurs as a result of metaplasia of squamous epithelial cell rests that are remnants of the part of the stomadeum that contributed to the buccal mucosa.

Epidemiology
The incidence of newly diagnosed craniopharyngiomas ranges from 0.13 to 2 per 100,000 population per year, with a point prevalence of 1 to 3 per 100,000 population [1-3]. There is no variance by gender or race. Distribution by age is bimodal with the peak incidence in children at 514 years and in adults at 6574 years of age. In children, craniopharyngiomas account for 5% of all tumours and 50% of all sellar/para sellar tumours [1,3].

Clinical description
Craniopharyngiomas are generally slow growing tumours. Symptoms develop insidiously and there is often a delay of 12 years between symptom onset and diagnosis. The usual symptoms on presentation are [4,5]:
Raised intracranial pressure headaches, nausea and vomiting either from mass effect from the tumour itself or from secondary hydrocephalus caused by obstruction of the foramen of Monro, the third ventricle or the aqueduct of Sylvius Endocrine dysfunction normally suppressed endocrine function, for example hypothyroidism, orthostatic hypotension, short stature, diabetes insipidus, impotence and amenorrhoea, but there can be an exaggeration of endocrine function, for example precocious puberty in children and obesity in adults. Visual disturbance classically a bitemporal hemianopia from inferior chiasmatic compression but alternatively patients may have a homonymous hemianopia, scotoma and optic atrophy with papilloedema.

Diagnostic methods
The diagnosis of a patient with a craniopharyngioma is based on clinical and radiological findings and is then confirmed by characteristic histological findings. The evaluation of a patient with a probable craniopharyngioma consists of [4]:
Imaging The classical appearance of a craniopharyngioma is of a sellar/para sellar part solid, part cystic calcified mass lesion. These tumours occur in the supra sellar (75%), supra and infra sellar (20%) and infra sellar (5%) regions [7]. The supra sellar tumours may be subdivided into further groups depending on their relationship to the third ventricle and the optic chiasm [8]. The calcification is best delineated on computerised tomography (CT) (Figure 1). Magnetic resonance imaging (MRI) with and without contrast will, however, more accurately delineate the extent of the tumour and, in particular, its involvement with the hypothalamus (Figure 2). It is the investigation of choice to plan the surgical approach. Magnetic resonance angiography (MRA) is useful to not only delineate the course of the vessels, which can be through the tumour, but also to help differentiate a tumour from a possible vascular malformation [7]. Endocrine assessment The hypothalamic-pituitary axis hormones, namely growth hormone, thyroid hormone, luteinising and follicle stimulating hormone should be measured together with cortisol levels and an assessment of serum and urine osmolality. In addition, an estimate of bone age and, for young females, ovarian ultrasonography is useful. Ideally, any abnormalities should be corrected pre-operatively but, at the very least, low cortisol levels and diabetes insipidus should be treated prior to a surgical procedure [9].

Other presenting symptoms include chemical meningitis (from rupture of cyst contents into the subarachnoid space), seizures, poor school performance in children or emotional lability and apathy in adults.

Aetiology
There are two histological phenotypes seen in craniopharyngioma: i) the adamantinomatous tumours, seen in children, that resemble enamel forming neoplasm's in the oropharynx and ii) the squamous papillary form, predominantly seen in adults. The characteristic location of these tumours in the sellar and para-sellar region, together

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Figure CT of a 1 craniopharyngioma CT of a craniopharyngioma. This unenhanced CT shows a calcified cystic structure in the supra sellar region, together with hydrocephalus

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Figure 2 T1 weighted MRI's of craniopharyngiomas Enhanced Enhanced T1 weighted MRI's of craniopharyngiomas. a. Apredominantly solid sellar/supra sellar tumour that is discrete fromthe hypothalamus (grade 0). b. A predominantly cystic sellar/suprasellar tumour that is distorting but not invading the hypothalamus (grade 1). c. A predominantly solid sellar/supra sellar tumour. The hypothalamus is not visible because of tumour invasion (grade 2).

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Ophthalmology assessment Visual acuity and visual field assessment is required to delineate any deficit (e.g. field defects, central scotoma). In addition, visualisation of the optic discs, to exclude papilloedema, and visual evoked potentials should be performed. Histology The tumour cells are small and have an epithelial appearance. Numerous micro cystic spaces are formed. Additional findings include hyalinised calcified structures, collagen, fibroblasts, foreign body giant cells and occasionally cholesterol clefts.

optic pathways and/or to re-establish the cerebrospinal fluid (csf) pathways, followed by radiotherapy [19-24]. The second pathway was developed because of the high morbidity experienced with the gross total resection of tumours that invade the hypothalamus [25-27]. The morbidity can be considered in terms of hypothalamic dysfunction and an altered neuropsychological profile [2833]. In an attempt to balance the advantages of an aggressive surgical resection against the risk of significant morbidity associated with this, a pre-operative grading system has recently been proposed that considers the extent of invasion of the hypothalamus by the tumour as opposed to the traditional anatomical localisation [34]. In this grading, type 0 represents no hypothalamic involvement, in type 1 the tumour distorts or elevates the hypothalamus, but the latter is still visible, whilst in type 2 tumours the hypothalamus is no longer visible (Figure 2). In a cohort of 66 paediatric patients there was a significant relationship between a higher the pre-operative grade and a higher rate of post-operative morbidity. Consequently, it was proposed that a gross total resection should be attempted in type 0 and 1 tumours and a sub-total resection, leaving only the hypothalamic component of the tumour, in patients with a type 2 tumour [34]. It should be noted, however, that the gross total removal of a tumour that is not invading the hypothalamus or a subtotal resection leaving only the hypothalamic component of the tumour, is not without its risks. Furthermore, surgical experience has been noted to have a significant impact, justifying the management of these patients in a centre that has a particular interest in them [34]. Whilst this grading system was developed in a paediatric population, it could equally be applied to an adult population. There is some evidence, however, that the craniopharyngiomas that arise in adults are less likely to invade the hypothalamus. Nevertheless, in recent large adult series only about 50% of patients are having a gross total resection, which is similar to paediatric series, because of the recognised significant morbidity associated with surgical injury to the hypothalamus [17,35]. Residual tumour, confirmed on post-operative MRI, is generally treated with external beam radiotherapy, however, stereotactic radiosurgery (gamma knife) has been used [36]. The use of proton beam radiotherapy for residual disease is currently being investigated [36]. Occasionally, a patient presents with a purely cystic tumour. The management options for these tumours also includes the stereotactic placement of a catheter to allow repeated aspiration. Furthermore, the use of intracystic radiotherapy (Yttrium-90 or Phosporus-32) [37] or chemotherapy (Bleomycin) [38] has had some success.

Differential diagnosis
The differential diagnosis may be considered under four main headings [4]:
Congenital anomalies Arachnoid cyst and Rathke's cleft cyst. Other Tumours Pituitary tumour, metastasis, meningioma, epidermoid and dermoid tumour, hypothalamic-optic pathway glioma, hypothalamic hamartoma, teratoma. Infectious/Inflammatory processes Eosinophilic granuloma, lymphocytic hypophysitis, sarcoidosis, syphilis and tuberculosis. Vascular malformations Aneurysm of the internal carotid or anterior communicating artery, arterio-venous malformation.

Genetic counselling
There is currently no known genetic relationship. There are, however, a few familial cases reported in the literature [10-12].

Management and treatment

The management of patients presenting with these unusual tumours should ideally be in a specialised centre that has a particular interest in them. The clinical presentation of patients may be as an emergency with symptoms of raised intracranial pressure or rapid deterioration in visual function. Initial surgical treatment, for hydrocephalus or tumour cyst decompression, to relieve these symptoms and prevent further visual deterioration may be necessary, prior to definitive treatment of the tumour. There are two main management pathways with regards to the treatment of the tumour. The first involves attempted gross total resection of the tumour [8,13-18], the second approach is for more limited surgery, aimed at debulking the tumour to reduce the mass effect on the

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There is no place for systemic chemotherapy, however recently the use of immunological therapy has been considered. Interferon alpha had a minimal effect when given systemically but there has been some success when used intracystically [39]. Post-operatively there is usually an improvement in visual deficits [22]. Lifelong follow-up by an ophthalmologist is however recommended. By contrast, the endocrine disturbances are likely to be permanent, if not exacerbated by surgery [40]. Obesity is present in 50% of patients, whilst about 80% of patients require two or more anterior pituitary hormone replacement therapy and permanent diabetes insipidus occurs in up to 75% of adults and 90% of children [30]. Lifelong review by an endocrinologist is clearly necessary.

tumour. There are, however, possible long-term complications with radiotherapy (cataracts, exacerbation of hypothalamic-pituitary dysfunction, cognitive dysfunction, radionecrosis) [21,43]. In a recently published series, 20% of patients with a sub-total resection remained stable during follow-up without radiotherapy [34]. It is currently unclear as to whether all patients with residual tumour should receive immediate post-operative radiotherapy. There is evidence that surgical experience has an impact on the clinical outcome of patients with a craniopharyngioma. The sub-total removal of a tumour that is invading the hypothalamus is not straightforward and yet it can be speculated that the smaller the residual component the greater the efficacy of the post-operative radiotherapy. Despite the use of radiotherapy for residual disease, in approximately 20% of patients the disease will recur [21,34]. The only option in these patients is for aggressive tumour removal. The long-term clinical outcome of these patients is currently unknown.

Prognosis and quality of life

The overall five-year survival is 80% but the survival is better in children (85% 5 year survival) than in older adults (40% 5 year survival) [3,16,17]. Survival, however, may be associated with marked disability. The historical treatment of patients with craniopharyngiomas has been described as a pendulum [41]. The gross total removal of a tumour that is invading the hypothalamus is technically demanding but achievable. There is, however, a definite mortality (up to 10%) with this procedure and despite a gross total resection a recurrence rate (up to 15%) [5,8]. The clinical outcome however can be less than ideal with hypothalamic dysfunction (hyperphagia, obesity, behavioural disorders, memory problems, loss of neurovegetative homeostasis) and an altered neuropsychological profile (marked distractibility, difficulties in perceptual organisation, poor verbal memory), that even with the use of hormonal replacement therapy, have a significant impact on daily activities in both adult and paediatric patients [28,29,33,42]. The pendulum has thus swung away from attempting gross total resection in those patients with hypothalamic invasion to a less radical approach. In these patients, the hypothalamic component of the tumour is left and treated with post-operative radiotherapy. There is some recent evidence in a paediatric population that the 5-year survival in patients with this dichotomised regime is 80%, in keeping with previously published series in which all the patients underwent a gross total resection [34]. Whilst there is no improvement in mortality using this treatment protocol, there is some evidence that there is reduced hypothalamic dysfunction in this population.

Abbreviations used in this paper (all defined in the text)

CSF : cerebrospinal fluid, CT : computerised tomography, MRA : magnetic resonance angiography, MRI : magnetic resonance imaging.

Competing interests
The author(s) declare that they have no competing interests.

Authors' contributions
MRG drafted the manuscript and all authors were subsequently involved in revising the manuscript critically for important intellectual content.

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