Orphanet Journal of Rare Diseasesvolume 2, Article number: 18 (2007)
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 sub-total 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).
Rathke's pouch tumour, craniopharyngeal duct tumour, adamantinoma, adamantinomatous tumour, dysodontogenic epithelial tumour.
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.
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.
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 5–14 years and in adults at 65–74 years of age. In children, craniopharyngiomas account for 5% of all tumours and 50% of all sellar/para sellar tumours [1, 3].
Craniopharyngiomas are generally slow growing tumours. Symptoms develop insidiously and there is often a delay of 1–2 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
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.
classically a bitemporal hemianopia from inferior chiasmatic compression but alternatively patients may have a homonymous hemianopia, scotoma and optic atrophy with papilloedema.
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.
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 with the different histological subtypes, allows for two theories that may explain the origin of these tumours :
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.
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 :
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 . The supra sellar tumours may be subdivided into further groups depending on their relationship to the third ventricle and the optic chiasm . 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 .
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 .
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.
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.
The differential diagnosis may be considered under four main headings :
Arachnoid cyst and Rathke's cleft cyst.
Pituitary tumour, metastasis, meningioma, epidermoid and dermoid tumour, hypothalamic-optic pathway glioma, hypothalamic hamartoma, teratoma.
Eosinophilic granuloma, lymphocytic hypophysitis, sarcoidosis, syphilis and tuberculosis.
Aneurysm of the internal carotid or anterior communicating artery, arterio-venous malformation.
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 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 [28–33].
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 . 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 . It should be noted, however, that the gross total removal of a tumour that is not invading the hypothalamus or a sub-total 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 . 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 . The use of proton beam radiotherapy for residual disease is currently being investigated .
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)  or chemotherapy (Bleomycin)  has had some success.
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 .
Post-operatively there is usually an improvement in visual deficits . Lifelong follow-up by an ophthalmologist is however recommended. By contrast, the endocrine disturbances are likely to be permanent, if not exacerbated by surgery . 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 . Lifelong review by an endocrinologist is clearly necessary.
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 . 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 . Whilst there is no improvement in mortality using this treatment protocol, there is some evidence that there is reduced hypothalamic dysfunction in this population.
It is generally recommended that radiotherapy is given following sub-total excision of a craniopharyngioma,. This will reduce the likelihood of growth of the residual 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 . 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.
cerebrospinal fluid, CT : computerised tomography, MRA : magnetic resonance angiography, MRI : magnetic resonance imaging.
Bunin GR, Surawicz TS, Witman PA, Preston-Martin S, Davis F, Bruner JM: The descriptive epidemiology of craniopharyngioma. J Neurosurg. 1998, 89: 547-551.
Daly AF, Rixhon M, Adam C, Dempegioti A, Tichomirowa MA, Beckers A: High Prevalence of Pituitary Adenomas: A Cross Sectional Study in the Province of Liege, Belgium. J Clin Endocrinol Metab. 2006, 12: 12-20.
Haupt R, Magnani C, Pavanello M, Caruso S, Dama E, Garre ML: Epidemiological aspects of craniopharyngioma. J Pediatr Endocrinol Metab. 2006, 19 (Suppl 1): 289-293.
Jagannathan J, Dumont AS, Jane JA Jr, Laws ER Jr: Pediatric sellar tumors: diagnostic procedures and management. Neurosurg Focus. 2005, 18: 1-5.
Karavitaki N, Cudlip S, Adams CB, Wass JA: Craniopharyngiomas. Endocr Rev. 2006, 27: 371-397. 10.1210/er.2006-0002.
Miller DC: Pathology of craniopharyngiomas: clinical import of pathological findings. Pediatr Neurosurg. 1994, 21: 11-17.
Rossi A, Cama A, Consales A, Gandolfo C, Garre ML, Milanaccio C, Pavanello M, Piatelli G, Ravegnani M, Tortori-Donati P: Neuroimaging of pediatric craniopharyngiomas: a pictorial essay. J Pediatr Endocrinol Metab. 2006, 19: 299-319.
Yasargil MG, Curcic M, Kis M, Siegenthaler G, Teddy PJ, Roth P: Total removal of craniopharyngiomas. Approaches and long-term results in 144 patients. J Neurosurg. 1990, 73: 3-11.
Hopper N, Albanese A, Ghirardello S, Maghnie M: The pre-operative endocrine assessment of craniopharyngiomas. J Pediatr Endocrinol Metab. 2006, 19: 325-327.
Combelles G, Ythier H, Wemeau JL, Cappoen JP, Delandsheer JM, Christiaens JL: Craniopharyngioma in the same family. Neurochirurgie. 1984, 30: 347-349.
Green AL, Yeh JS, Dias PS: Craniopharyngioma in a mother and daughter. Acta Neurochir (Wien). 2002, 144: 403-404. 10.1007/s007010200058.
Wald SL, Liwnicz BH, Truman TA, Khodadad G: Familial primary nervous system neoplasms in three generations. Neurosurgery. 1982, 11: 12-15. 10.1097/00006123-198207010-00003.
Dhellemmes P, Vinchon M: Radical resection for craniopharyngiomas in children: surgical technique and clinical results. J Pediatr Endocrinol Metab. 2006, 19 (Suppl 1): 329-335.
Hoffman HJ, De Silva M, Humphreys RP, Drake JM, Smith ML, Blaser SI: Aggressive surgical management of craniopharyngiomas in children. J Neurosurg. 1992, 76: 47-52.
Lapras C, Patet JD, Mottolese C, Gharbi S, Lapras C: Craniopharyngiomas in childhood: analysis of 42 cases. Prog Exp Tumor Res. 1987, 30: 350-358.
Tomita T, Bowman RM: Craniopharyngiomas in children: surgical experience at Children's Memorial Hospital. Childs Nerv Syst. 2005, 21: 729-746. 10.1007/s00381-005-1202-9.
Van Effenterre R, Boch AL: Craniopharyngioma in adults and children: a study of 122 surgical cases. J Neurosurg. 2002, 97: 3-11.
Weiner HL, Wisoff JH, Rosenberg ME, Kupersmith MJ, Cohen H, Zagzag D, Shiminski-Maher T, Flamm ES, Epstein FJ, Miller DC: Craniopharyngiomas: a clinicopathological analysis of factors predictive of recurrence and functional outcome. Neurosurgery. 1994, 35: 1001-1010. 10.1097/00006123-199412000-00001.
Cama A, Ravegnani M, Piatelli G, Rossi A, Gandolfo C, Garre ML: Conservative surgical approach in treatment strategy of craniopharyngioma: experience at a single institution in Italy. J Pediatr Endocrinol Metab. 2006, 19 (Suppl 1): 337-340.
De Vile CJ, Grant DB, Kendall BE, Neville BG, Stanhope R, Watkins KE, Hayward RD: Management of childhood craniopharyngioma: can the morbidity of radical surgery be predicted?. J Neurosurg. 1996, 85: 73-81.
Fischer EG, Welch K, Shillito J, Winston KR, Tarbell NJ: Craniopharyngiomas in children. Long-term effects of conservative surgical procedures combined with radiation therapy. J Neurosurg. 1990, 73: 534-540.
Habrand JL, Ganry O, Couanet D, Rouxel V, Levy-Piedbois C, Pierre-Kahn A, Kalifa C: The role of radiation therapy in the management of craniopharyngioma: a 25-year experience and review of the literature. Int J Radiat Oncol Biol Phys. 1999, 44: 255-263. 10.1016/S0360-3016(99)00030-9.
Merchant TE, Kiehna EN, Sanford RA, Mulhern RK, Thompson SJ, Wilson MW, Lustig RH, Kun LE: Craniopharyngioma: the St. Jude Children's Research Hospital experience 1984–2001. Int J Radiat Oncol Biol Phys. 2002, 53: 533-542. 10.1016/S0360-3016(02)02799-2.
Sanford RA, Muhlbauer MS: Craniopharyngioma in children. Neurol Clin. 1991, 9: 453-465.
Hayward R: The present and future management of childhood craniopharyngioma. Childs Nerv Syst. 1999, 15: 764-769. 10.1007/s003810050468.
Laws ER: Conservative surgery and radiation for childhood craniopharyngiomas. J Neurosurg. 1991, 74: 1025-1026.
Rutka JT: Craniopharyngioma. J Neurosurg. 2002, 97: 1-2.
Carpentieri SC, Waber DP, Scott RM, Goumnerova LC, Kieran MW, Cohen LE, Kim F, Billett AL, Tarbell NJ, Pomeroy SL: Memory deficits among children with craniopharyngiomas. Neurosurgery. 2001, 49: 1053-1057. 10.1097/00006123-200111000-00005.
Cohen RA, Albers HE: Disruption of human circadian and cognitive regulation following a discrete hypothalamic lesion: a case study. Neurology. 1991, 41: 726-729.
De Vile CJ, Grant DB, Hayward RD, Kendall BE, Neville BG, Stanhope R: Obesity in childhood craniopharyngioma: relation to post-operative hypothalamic damage shown by magnetic resonance imaging. J Clin Endocrinol Metab. 1996, 81: 2734-2737. 10.1210/jc.81.7.2734.
Lobosky JM, Vangilder JC, Damasio AR: Behavioural manifestations of third ventricular colloid cysts. J Neurol Neurosurg Psychiatry. 1984, 47: 1075-1080.
Poretti A, Grotzer MA, Ribi K, Schonle E, Boltshauser E: Outcome of craniopharyngioma in children: long-term complications and quality of life. Dev Med Child Neurol. 2004, 46: 220-229. 10.1017/S0012162204000374.
Sorva R, Heiskanen O, Perheentupa J: Craniopharyngioma surgery in children: endocrine and visual outcome. Childs Nerv Syst. 1988, 4: 97-99.
Puget S, Garnett MR, Wray A, Grill J, Habrand JL, Bodeart N, Zerah M, Renier D, Pierre-Kahn A, Sainte-Rose C: Childhood Craniopharyngioma: Classification and Treatment according to the degree of hypothalamic involvement. J Neurosurg. 2007, 106: 3-12.
Fahlbusch R, Honegger J, Paulus W, Huk W, Buchfelder M: Surgical treatment of craniopharyngiomas: experience with 168 patients. J Neurosurg. 1999, 90: 237-250.
Habrand JL, Saran F, Alapetite C, Noel G, El Boustany R, Grill J: Radiation therapy in the management of craniopharyngioma: current concepts and future developments. J Pediatr Endocrinol Metab. 2006, 19: 389-394.
Kalapurakal JA: Radiation therapy in the management of pediatric craniopharyngiomas–a review. Childs Nerv Syst. 2005, 21: 808-816. 10.1007/s00381-005-1188-3.
Hargrave DR: Does chemotherapy have a role in the management of craniopharyngioma?. J Pediatr Endocrinol Metab. 2006, 19: 407-412.
Cavalheiro S, Dastoli PA, Silva NS, Toledo S, Lederman H, da Silva MC: Use of interferon alpha in intratumoral chemotherapy for cystic craniopharyngioma. Childs Nerv Syst. 2005, 21: 719-724. 10.1007/s00381-005-1226-1.
Cavazzuti V, Fischer EG, Welch K, Belli JA, Winston KR: Neurological and psychophysiological sequelae following different treatments of craniopharyngioma in children. J Neurosurg. 1983, 59: 409-417.
Sainte-Rose C, Puget S, Wray A, Zerah M, Grill J, Brauner R, Boddaert N, Pierre-Kahn A: Craniopharyngioma: the pendulum of surgical management. Childs Nerv Syst. 2005, 21: 691-695. 10.1007/s00381-005-1209-2.
Sano K, Mayanagi Y, Sekino H, Ogashiwa M, Ishijima B: Results of stimulation and destruction of the posterior hypothalamus in man. J Neurosurg. 1970, 33: 689-707.
Paulino AC, Fowler BZ: Secondary neoplasms after radiotherapy for a childhood solid tumor. Pediatr Hematol Oncol. 2005, 22: 89-101.
The author(s) declare that they have no competing interests.
MRG drafted the manuscript and all authors were subsequently involved in revising the manuscript critically for important intellectual content.