Craniopharyngiomas are the commonest of a heteregenous group of tumors that have in common their congenital origin and slow rate of growth. They have always been one of the most controversial problems of neurosurgery concerning their origin, optimal therapy, operative approach, and response to radiation. Craniopharyngiomas are still one of the most challenging tumors for neurosurgeons. Despite the significant technical advances in microneurosurgery, radiation therapy and endocrinology, the controversies have not abated.

Controversies apart, for all practical purposes, they are better considered as true neoplasms, rather than an hamartoma or a cyst. Rightly, WHO has listed them as sellar tumors, although purists may not agree.

Incidence:

Craniopharyngiomas constitute between 2.5-4% of all intracranial tumors. There are 0.5-2 new cases per million populations occurring each year. Almost 50% are in adults. Craniopharyngioma is the most common tumor of non-glial origin in children representing 54% of all suprasellar tumours in childhood and 20% of those in adults.

They may present at any age with preponderance in childhood. The highest peak of incidence is between the ages of 5 and 10, a moderate peak exists among adults in the 4th and 5th decade. The tumor occurs with equal frequency in both sexes in all ages.

Pathology:

Since the anatomical structures in the suprasellar region are normally devoid of epithelial cells such as those seen in craniopharyngiomas, the nature and source of these cells have long been the subject of intensive investigation. In 1899, Mott and Barrett stated that Craniopharyngiomas may arise from the hypophyseal-pharyngeal duct or Rathke’s pouch. In addition, Erdheim demonstrated in 1904 that these are epithelial tumors arising from embryonic squamous cell rests of the incompletely involuted hypophyseal-pharyngeal duct located in the pars tuberalis and along the pituitary stalk. This theory continues to be widely accepted. However, since squamous cell rests are rarely found in neonates, and their presence increases with age, some argue that these tumors are not originated from those embryonic rests, but may arise by metaplasia of normally developed anterior pituitary cells.

Craniopharyngiomas are histologically benign tumors of epithelial origin involving primarily the sellar region with a tendency to adhere to vital neural and vascular structures. Although usually well circumscribed and extracerebral in location, they often extend into the neighboring brain tissue evoking a variable degree of glial reaction. They may also be strongly adherent to major arteries and cranial nerves at the removal difficult and sometimes impossible. Postoperative complications and tumor recurrence are frequent. Consequently, this benign tumor is often malignant in clinical behavior.

Craniopharyngiomas are mostly located in the suprasellar region and grow by expansion into the hypothalamus and third ventricle upwards, growing into the sella, down between the clivus and brainstem, or even into the cerebelloprontine cistern. There are some rare primary locations, such as: intrasellar, within the third ventricle, nasopharyngeal, craniobasal, and pineal. Occasionally they may be enormous. Occlusion of the CSF pathways with subsequent hydrocephalus occurs in 15 to 30% of the cases.

The macrosocpic appearance of craniopharyngiomas is wholly cystic in 34%, purely solid in 23% and mixed in 43%, thus about 77% tumors are cystic. The fluid in these cysts is oily yellow, brown, or greenish. This solution contains variable amounts of protein with suspended cholesterol crystals which are birefringent to polarized light is viscosity varies from watery to viscous. Cyst walls may be transparent membranes or dense, tough structures. Calcification is found in about half of adult craniopharyngiomas and in almost all children.

Histology: Craniopharyngiomas are generally composed of mature epithelial cells with an external layer of high columnar epithelium, a variable portion of polygonal cells and a central network of epithelial cells, without any sign of malignant heterogeneity, cellular atypia or mitoses. This structure is supported by variable amounts of loose growth of these tumors is not neoplastic, but results from simple cellular proliferation of the epithelium, desquamation, degeneration and colliquation of the epithelial cells with active sequestration of cystic fluid. Regressive changes in the epithelial cells include cellular liquefaction resulting in cyst formation or deposition of a keratin-like material or calcium salts resulting in calcification.

There are two basic craniopharyngioma variants, the adamantinous and squamous papillary type. There is a correlation between the histopathological, clinical, and prognostic features of the two histological types. The behavior of childhood craniopharyngioma is distinctly different from that in adults.

Symptoms and signs:

The clinical signs are due to the location of the tumor, though adults and children may have different clinical syndromes. The multiplicity of possible directions of growth of these tumors is mirrored by a corresponding variation in the clinical pictures they may present.

Children: Since these tumors may reach a large size before causing symptoms in children, they usually present with signs of increased intracranial pressure mainly due to occlusion CSF pathways and secondary hydrocephalus or due to the size of the cyst. Disturbances of hypothalamic-pituitary function such as growth failure, pituitary dwarfism, hypogonadism, delayed puberty, diabetes insipidus, genital dystrophy are also characteristic in about 93%. Visual loss and visual field defects are usually found at examination, though children tolerate remarkable degrees of visual loss without complaint.

Adults: Visual impairment and visual field defects (mostly bitemporal hemianopia) are characteristic complaints in adults, but any combination of visual symptoms can be present, similar to those of a pituitary adenomas. Papillioedema is uncommon, but optic atrophy is frequent in both age groups. Progressive visual failure requires urgent treatment in many cases. Psychiatric symptoms include personality changes, dementia memory loss, drowsiness, confusion, depression, hyperphagia, aggression which can develop in association with obstructive hydrocephalus and with hypothalamic dysfunction. Patients frequently (85%) present with endocrinopathies such as menstrual irregularities, loss of libido, diabetes insipidus, hypothyrodism, hypodrenalism, and obesity. Symptoms suggesting intracranial hypertension often prompt patients to seek medical attention. Spontaneous rupture of craniopharyngioma cysts is extremely rare; only a few cases have been reported causing chemical meningitis with temporary alleviation of headache and improvement in visual disturbance.

Differential diagnosis:

In Children: Hypothalamic and optic gliomas, Germinomas, Hamartomas, Teratomas, Pituitary adenomas, Histocytosis X, Chordomas, Ectopic pinealomas, Primitive neuroectodermal tumours

In adults: Pituitary adenomas, Rathke’s cleft cyst, Epithelial cyst, Meningioma, Epidermoid, Dermoid, Arachnoid cyst, Cavernous angioma, Colloid cyst, Tuberculoma, Metastasis, Internal carotid artery aneurysm.

Diagnosis:

There are a number of neuroimaging methods to reveal the craniopharyngiomas surgically important features as well as to differentiate them from other possible suprasellar masses.

Plain skull X-rays show pathological changes in most of the adult and almost all of the pediatric cases. Tumor calcification is found on X-ray in 85% of the pediatric and 405 of the adult cases. Other signs include enlarged sella, bony erosion of the sella, dorsum, or clinoids, and signs of increased ICP.

CT scan shows the extent of the lesion, distinguishes between solid, cystic and calcified components and demonstrates hydrocephalus. The appearance of the cyst fluid is variable. It is usually of low density, but can be isodense or hyperdense if it contains sufficient protein and suspended calcium salts. The solid portions of craniopharyngiomas are either isodense or slightly hyperdense. Contrast administration mostly causes intensive heterogeneous enhancement. Ring-shaped contrast enhancement can sometimes be seen around cysts. Coronal scanning helps to identify intrasellar extension, relation to the third ventricle and impingement of tumor on the basal brain parenchyma.

MRI is superior to CT in demonstrating the general configuration of the tumor mass, with us relationship to the ventricular system, major nerves and cranial arteries. It characteristically shows a heterogeneous suprasellar mass containing cysts and empty holes correlating with calcification. Cysts usually appear bright on T2-weighted sequences. The signal intensity of the fluid varies on T1-weighted images from hyperintense to hypotense, reflecting the heterogeneous contents of cysts. Cysts with a low protein content are indistinguishable from cysts of other etiology. Calcification produces a low signal on MR images, which are less specific in this respect than CT scans. Solid tumor components present a less well-defined margins compared to pituitary adenomas. These areas intensively enhance with gadolinium contrast on T1 weighted studies.

Angiography has become redundant these days.

Management:

The treatment of cranipharyngioma remains controversial, reflecting the difficulties in management as well as the heterogeneity of these tumors. 15 to 30% of the patients require attention to associated hydrocephalus.

In most cases, cranipharyngiomas can be removed totally or subtotally even when they have reached a great size. There is little doubt that an initial total tumor excision yields the best long term outcome if it can be achieved without neurological sequelae. Some workers regard surgery of carniopharyngiomas as merely palliative and believe that subtotal or partial resection followed by radiation therapy should be the rule.

While total removal may be associated with significant endocrine alterations and hypothalamic disturbances, subtotal removal results in higher rates of recurrence.

Most reviews conclude that total excision should be attempted whenever feasible, and subtotal removal with adjuvant radiation should be done when total resection is dangerous. In cases of recurrence, radical tumor removal, subtotal resection and/or irradiation are again the usual treatment modalities.

Adjunctive therapy should be reserved for recurrent or predominantly cystic cases.

Strict endocrinological evaluation and hormonal replacement regiments are essential in all patients in both the immediate and long term postoperative period. (refer to pituitary adenoma)

Multimodality therapy is often necessary over the course of a patient’s lifetime. Due to the diverse nature of craniopharyngiomas, therapy must be individualized to the particular clinical problem by following the natural history of each case.

Surgical approaches:

There are several operative approaches to craniopharyngiomas. Each has its own advantages and disadvantages. The side of the craniotomy is determined by considering various factors such as visual acuity and field defect, lateralization of cyst, calcification and/or solid mass, lateralization of the compromised hypothalamus, and the preference of the surgeon.

Unilateral operations are preferable.

a) The pterional (frontotemporal) approach provides access to virtually all parts of even very large tumors.  It is the shortest route to the parasellar region and allows good visualization of the retrosellar area; but  visualization of the contralateral optic nerve is limited.

b) The unilateral or bifrontal subfrontal approach allows good visualization of optic nerves, chiasm and ipsilateral carotid artery, making the presellar anatomy easily understandable.  On the other hand, it does not give good access to the area beneath the ipsilateral optic nerve and tract, and the region of the third ventricle.

c) The transcallosal approach uses a fronto-parasagittal craniotomy.  This route is preferable when the tumor is within or in the region of the third ventricle and the tumor pushes the anterior hypothalamus forwards.  In these situations a basal approach would result in damage to the hypothalamus before the tumor has been reached. This approach offers good visualization of both walls of the third ventricle. Anterior corpus callosum needs to be divided and there is a risk of bilateral fornix damage.

d) The transcortico-ventricular approach is associated with a cortical incision, requires the presence of hydrocephalus, and allows limited visualization within the third ventricle.  This offers good visualization of the ipsilateral foramen of Monro.This technique has been largely abandoned.

e) Transsphenoidal surgery avoids craniotomy and is best reserved for patients with enlarged sella and intrasellar infradiaphragmatic, primarily cystic craniopharyngiomas. Enlargement of the sella is of primary importance when using this approach, since it implies that the tumor took origin under the diaphragma sellae, thus it is not attached to the suprasellar structures such as the chiasm or hypothalamus, making total removal possible.  This approach is also used to drain cystic tumors, and as part of staged surgery in partially intrasellar tumors.

Tumor dissection uses combinations of routes.

The interoptical route, between the optic nerves, gives an excellent view of both carotid arteries.  The optic carotid pathway lies between the carotid artery and the optic nerve and tract. 

Intraventricular craniopharyngiomas can be approached through the lamina terminalis.  This pathway permits visualization of the anterior third ventricle and gives access to supra- and retrochiasmatic masses, but carries the highest risk of hypothalamic damage.. 

The lateral and clival tumor surface can be approached between the carotid artery and oculomotor nerve.

The intracranial transsphenoidal pathway requires drilling partially away the tuberculum sellae and the anterior wall of the sellae and opening the sphenoid sinus without disrupting its mucosal membrane.  This can be useful when the tumor has a deep intrasellar extension, and when the chiasm is prefixed.

In cases of hydrocephalus, primary tumor removal usually re-establishes normal CSF pathways avoiding shunting.  However, when the hydrocephalus is pronounced ventricular shunting may be performed as a first step.

The surgeon should be familiar with these approaches and should use a combination of these techniques as necessary.

Surgical technique:

Once all the major neural and vascular structures are identified, each of the possible routes of approach is evaluated and the greatest possible tumor surface is exposed. Since these are subarachnoid tumors, the preservation of the plane between the tumor capsule and the arachnoid is essential for safe and total tumor removal. Besides general brain protection, the entire intradural area is lined with cotonoids to prevent the spread of the irritating crystalline content of cyst or solid tumor on to the brain or into the CSF, as it may lead to an aseptic meningitis or hydrocephalus postoperatively.

The optic nerves and chiasm are most often found to be stretched anterosuperiorly by the pressure of the tumor. After additional manipulation, any residual function may be lost. Upwards displacement of the optic nerves against the sharp upper edge of the optic foramen invariably results in visual loss. Before causing more damage to the optic nerve, the foramen should be decompressed at an early stage by partly removing its bony roof and opening its dural sleeve.

The usually severely compressed pituitary stalk and infundibulum may be found displaced behind, above or lateral to the tumor. Preservation of the stalk, in cases when it is not destroyed by the tumor, may occasionally be possible. Although it may be functionally disconnected by the tumor compression and surgical manipulation, a remnant of stalk reaching from the medial eminence to the pituitary gland may serve as a matrix upon which the pituitary portal system may reform.

Aspiration of any cyst is the first step. The arachnoid covering of the tumor is carefully opened. Entering the tumor with a microsuction tip will further decompress the tumor. As the tumor mass decreases, more of the arachnoid capsule may be exposed by dissecting in the plane around the tumor. Craniopharyngiomas tend to get their arterial blood supply from the vessels of the anterior circle of Willis. Direct branches from the carotid, the anterior cerebral and the posterior communicating arteries have been described. Within the sella turcica the tumor may be supplied by small perforating branches directly from the cavernous portion of the internal carotid artery. They do not receive blood from the posterior cerebral or basilar arteries unless the third ventricle is invaded. These feeders may be coagulated and divided. The interior of the tumor is entered and the solid portion removed piecemeal. As the tumor is progressively gutted, the capsule may be gradually resected.

Every effort should be made to preserve the arachnoid capsule so that leaving behind torn-off bits of the capsule is avoided. Even the tiniest scrap left behind can cause tumor recurrence. Using small angled dental mirrors is recommended to gain vision to the undersurface of the optic apparatus and hypothalamus. Use of endoscope is a better option.

Tenacious adhesions of tumor to main and perforating arteries, usually on the anterior circle of Willis, are the most common obstacle to achieving total removal. This mesenchymal reaction to the craniopharyngioma capsule appears to be denser than the glial scar that forms underneath the chiasm or hypothalamus.

Intraoperative arterial damage should be avoided during dissection of these adherent parts.

Large solid calcified portions can be difficult to break up and remove as they may pose a risk to the neural and vascular structures as the jagged pieces of calcified material are delivered past them. Calcified tumors, particularly those adherent to or enclosing vital structures, have a lesser chance of total removal.

In tumors that infiltrate the hypothalamus it may be found that in some cases these structures can be easily preserved, while in others it is impossible to distinguish between the normal hypothalamus, the gliotic tissue and the tumor. The ease of removal and risk of dissection can vary accordingly. A dense, invasive finger-like tumorous and gliotic tissue with diffuse adhesions of the hypothalamus renders it impossible to follow a plane of cleavage. This situation limits the total respectability of these tumors.

Operative complications:

a) Preoperative endocrine deficiencies are irreversible in most cases. Surgical intervention, however, often leads to additional endocrine disorders. After craniopharyngioma surgery most patients have temporary or permanent disruption of neurohypophyseal axis function even if function was normal preoperatively. Among the various endocrine abnormalities, the loss of ADH and ACTH will be the most important in the postoperative period. Diabetes insipidus monitoring and therapy, and prophylactic treatment with corticosteroid are essential. Long term endocrine follow-up with appropriate replacement therapy is required with special attention in children.

b) Surgical manipulation of these tumors may result in hypothalamic dysfunction. Damage to the hypothalamic nuclei and varying range of deficits such as sudden death, alterations of consciousness ranging from somnolence to coma, water and electrolyte imbalance, loss of thirst, hyper-, hypo-,or poikilothermia, cardiac disturbances, hyperphagia, obesity, insomnia, hypogonadism, growth failure.

c) Disturbance of hypothalamic connections to the thalamus, limbic system, frontal lobes and other cortical areas may explain some of the psychiatric and social problems seen following treatment of cranipharyngiomas. Injury in this area, from surgical or less frequently from irradiation treatment, will result in problems common among these patients: confusion, short term memory loss, mutism, emotional and sexual immaturity, psychic imbalance, hyperphagia and aggressiveness.

d) Visual impairment is a relatively common surgical complication but can be minimized with technique. Direct surgical manipulation of the stretched optic nerve, chiasm and tract or their vascular supply may result in additional visual loss. Its reported incidence ranges from 1 to 17%. The degree of preoperative visual loss and its duration (optic atrophy) are the most important factors in determining postoperative visual status.

e) Three types of vascular lesions have been described after craniopharyngioma removal. The first is fusiform dilatation of the internal carotid artery which may develop due to the weakness of the arterial wall following dissection of the adherent tumor from the adventitia, or due to the injury of the vasa vasorum. Secondly ischemic symptoms may develop at sites distant from the operative field which is thought to result from the development of vasospasm related to the operative manipulation to the vessels, to the blood appearing in the subarachnoid space or possibly to some chemical substances of the spilled cyst fluid. Finally, in cases of massive hydrocephalus, intraoperative ventriculostomy can cause sudden collapse of the cortex with subsequent stretching of the cortical and bridging veins and multiple venous infarcts over the surface of the cortex.

f) CSF rhinorrhoea and meningitis are the most common complications of the transsphernoidal approach.

g) Other possible postoperative complications such as cranial nerve palsies, epilepsy and hemiparesis are related to the location and not the nature of this tumor.

Operative results:

At present, overall mortality for  total removal of craniopharyngiomas is under 10% in experienced hands.

There is a strong correlation between the size of the tumors and the outcome. Tumors smaller than 4 cm are usually totally removed with good to excellent results, while total removal of large (>4cm) tumor is associated with significantly higher morbidity and mortality. These facts stress the importance of early diagnosis and treatment of craniopharynigomas.

Virtually every series of craniopharyngiomas has reported recurrences of tumor even after a macroscopic total removal. Although these tumors are known as slow growing tumors, they tend to recur early because of the capacity for rapid growth of the cystic portions.

In different series, the majority of recurrence was noted within 2 years of surgery, though recurrences have been reported as late as 30 years after operation. In one study, 52.5% recurred within one year, 75% within 3 years and 85% within 5 years.

Reoperation and/or adjuvant irradiation are recommended in cases of symptomatic recurrences. Surgery of recurrent craniopharyngiomas has worse outcome in all series. The reported mortality rates are much higher, being between 12 and 38% (Samii, 1995). Recurrent tumors are more tightly adherent to vascular and neural structures, making total excision more dangerous and therefore impractical in many cases.

Yasargil (144 cases, 1990) achieved total primary removal of craniopharyngiomas in 90%. Primary radical excision without additional radiotherapy was associated with a good outcome in 76.8%, morbidity of 13.4% and an overall mortality rate of 9.8%. The recurrence rate was zero in the squamous papillary tumor group, 11% in the adamantinous group with a mean follow up period of 7.5 years. The squamous papillary tumors were more benign with a good outcome in 84.6%, and poor in 15.4%, without mortality. Adamantous tumors fared worse with a good outcome in 51.6% in adults and 73.9 % in children, mortality of 16.2% in adults and 6.5% in children. In Hoffman’s review (1992) of 50 pediatric cases, radical excision was possible in 90%, with a mortality rate of 6%. The recurrence rate among these children was 34% with a mean follow up period of five years. Symon (1991) reported 50 mostly adult cases of totally removed craniopharyngiomas with a mortality rate of 4% and major morbidity rate of 15%. The recurrence rate in his series was 6% within the mean follow up period of 30 months.

These authors and their results suggest that an attempt at total removal imposes no greater burden upon these patients as a result of neural or endocrine damage than other therapeutic modes would do.

Subtotal removal with radiotherapy:

Most widely practiced.

When the goal of total surgical removal is not reached, radiation therapy has the power both to improve the survival and to prolong the interval preceding recurrence. Radiation seems to be the best method of gaining control of tumor left in situ.

Proponents of primary subtotal or partial removal of craniopharyngiomas with radiation therapy believe that their results are superior in outcome to those of radical surgery with significantly less morbidity and mortality.

On the other hand, radiation therapy just retards the regrowth of craniopharyngiomas, but is rarely curative, and can lead to further endocrinological visual and psychosocial compromise, especially to the immature brain. It does not reverse most of the pre-treatment deficiencies, and carries the risk of development of radiation-induced necrosis and neoplasms such as gliomas and sarcomas.

Radiation-related morbidity correlates strongly with the given radiation dose. In Regine’s report (1993), 44% of all patients receiving tumor doses of < 54 Gy developed recurrence after this treatment, while only 16% of those receiving more than 54 Gy. However, any possible benefit in tumor control with doses above 60 Gy at 1.8Gy per fraction appears to be offset by the increased risk of radiation injury.

Those patients in whom removal is deemed to be total should not be irradiated. Because of the long-term effects of radiotherapy, some workers do not administer it unless there is a symptomatic recurrence. Because the risk of further endocrine and psychological injury by irradiation is related to the age of the patient, it may be advisable to delay radiation therapy in children for as long as possible.

In Wens’ series (1992) of 34 cases, total excision resulted in 20% recurrence rate, subtotal removal in 60%, and subtotal resection with radiation in 12.5% recurrence rate within a mean follow up of 6.4 years. Wen concludes that subtotal removal with radiotherapy is a significantly better mode of treatment.

In Fischer’s series (1990), management of childhood craniopharyngiomas was weighed toward subtotal operations with irradiation. His series mortality of 8% and the recurrence rate of 14%, as well as the social quality of life, are comparable to or even better than the results of the more radically oriented series.

Carmel reported (1982) the 10 year survival rate to be 52% with subtotal removal alone and 87% with subtotal surgery plus irradiation. Tumors recurred within 10 years in 50% of those presumed to have had total removal, in more than 90% of those subtotally removed and in less than 25% of those after subtotal removal and irradiation.

Unfortunately there have been no prospective studies comparing the efficacy of various treatment modalities in craniopharyngioma.

Other modalities:

Instillation of radioactive substances into the cyst isotopes such as yttrium-90 or phosphorus-32 into craniopharyngioma cysts using sterotaxy can successfully improve the clinical condition and survival. About 60% of craniopharyngiomas are mainly cystic, and this rate is higher in cases of recurrence. Injections of colloidal these implanted isotopes directly destroy the epithelial lining of the cysts, and cause accumulation of collagen fibres, hyaline degeneration and vascular occlusion, thus indirectly damaging the secreting tumor cells. Follow up diagnostic studies show gradual cyst regression, which commences a few months after installation, with cyst obliteration in 75% of the cases. A precise knowledge of the cyst volume is necessary to determine the amount and dosage of radioactive isotope to be injected. The optimum dosage of radionuclide should be sufficient to destroy cyst epithelium while minimizing damage to surrounding structures.

Intracavitary brachytherapy can be combined with external fractionated radiation therapy to address the solid components of the tumor not treated by the beta-radiation emitter. Like surgery, visual improvement is likely in patients with moderate deficit, but is less evident in patients with severe visual loss, while endocrine deficiencies seldom change.

Cyst drainage (Percautaneous) drainage of a unilocular cyst by means of a sterotactically implanted catheter, linked to a subgaleal reservoir allows periodic aspiration of the cyst fluid. This technique also allows the placement of radioactive or chemotherapeutic substances into the cystic tumor in temporary or permanently inoperable cases this modality seems to offer a safe alternative.

Radiosurgery should be considered in cases when the solid component of primary or residual tumor is smaller than 2.5 cm in the longest diameter. It is a primary treatment alternative for elderly or medically infirm patients, or for those who refuse surgery. Further follow-up is necessary to evaluate the long-term tumor control rate and the tolerance of surrounding critical structures.

Chemotherapy: Intracavitary installation of bleomycin and methotrexate has been reported with promising results. These agents might work by decreasing the secretion of cystic fluid and causing tumor cell degeneration. Systemic chemotherapy of craniopharyngiomas has been used sporadically in patients who refused other methods, with some merit.

These results warrant further evaluation of the effect of chemotherapy on craniopharyngiomas.