Embryology and Histogenesis

Craniopharyngioma is thought to arise from ectodermally derived epithelial cell remnants of Rathke’s pouch and the craniopharyngeal duct. Neoplastic transformation of cells derived from tooth primordia gives rise to adamantinomatous craniopharyngioma, whereas such transformation in cells derived from buccal mucosa primordia gives rise to the papillary type.¹⁶ By the fourth week of gestation, invagination of the stomodeum, lined by epithelial cells, takes place. This upward migration is met by a downward movement of neuroepithelium from the hypothalamus. This upward invagination, termed Rathke’s pouch, is responsible for development of the adenohypophysis, whereas the downward growth of neuroepithelium is the precursor of the future neurohypophysis.

As Rathke’s pouch meets the infundibulum, it separates from the stomodeum and rotates around the anterolateral surface of the infundibulum. This rotation, which occurs during formation of the adenohypophysis, is responsible for delivering embryonic rests to suprasellar or parasellar locations. This migration pathway from the primitive oral cavity is termed the craniopharyngeal duct. In 1904, Erdheim reported that the origin of craniopharyngiomas was based on incomplete involution of this pathway.¹⁷

Recent evidence supports the hypothesis that embryonic rests of cells from the craniopharyngeal duct produce the pituitary gland, Rathke’s pouch, and craniopharyngiomas.¹⁸ Both human chorionic gonadotropin and P-glycoprotein have been demonstrated to be produced by all these structures.^18,19

Challenges to the craniopharyngeal duct hypothesis have centered on evidence that children younger than 10 years rarely have any squamous cell rests around the pituitary. It has been demonstrated that only 3% of neonates harbor these cell rests; however, they are found more often in older individuals.^20,21

The second major hypothesis proposed for the pathogenesis of craniopharyngioma centers on the premise that existing cell rests in the adenohypophysis undergo metaplasia. This concept partially accounts for the observation that squamous papillary tumors occur predominantly in adults and lack any resemblance to tooth-forming epithelium. Arguments against this hypothesis are based on evidence that mixed tumors demonstrating both adamantinomatous and papillary squamous characteristics exist.^22,23

Epidemiology

Signs and Symptoms

Given the predominant location of these tumors in the sellar/parasellar region, craniopharyngioma is characteristically manifested as three clinical syndromes: visual dysfunction, disturbance of the hypothalamic-pituitary axis, and raised intracranial pressure as a result of obstruction of flow of cerebrospinal fluid (CSF) and hydrocephalus.^26,45–47 The median duration of symptoms in a series of 34 adult patients was 10 months. The pediatric cohort of patients in this mixed series had a median symptom duration of just 3 months.⁴⁸ Adults are more likely than children to have symptoms of visual or endocrine abnormalities, whereas children more often have symptoms of increased intracranial pressure. In adults, headache, vomiting, and visual disturbance (hemianopia, uniocular visual loss, and diplopia) are the most common initial complaints.⁴⁹ More than 80% of adult patients complain of some visual loss at initial evaluation and have evidence of a visual deficit on formal testing. In children, the most common initial symptom is headache, which occurs in 50% to 80%,^26,50 followed by vomiting (21% to 68%) and visual deterioration (47% to 80%).

The most common neurological signs relate to visual disturbance: visual field defects (35% to 79%), papilledema (10% to 50%), optic atrophy, and eye movement disorders. In adult patients, 29% have evidence of papilledema at initial encounter, compared with more than 50% in the pediatric population.⁴⁸ In very young children, increased head circumference or a bulging fontanelle may be seen. Ataxia is described in about 20% of instances.

Approximately 30% of adults will initially have symptoms of endocrine disturbance.⁵¹ Gonadal insufficiency is the most common endocrine abnormality at diagnosis and consists of loss of libido and reduced masculine hair growth pattern in men. Women may complain of irregular menstrual periods or even amenorrhea. Other endocrinologic problems at initial evaluation include diabetes insipidus, hyperprolactinemia, adrenal insufficiency, and thyroid insufficiency.

Less than 15% of children with craniopharyngioma have complaints attributable to an endocrinologic deficit,⁵² even though almost 90% have some endocrine abnormality. Delayed puberty (4% to 24% of patients), obesity (8% to 15%), anorexia, short stature, and precocious puberty are all potential manifestations of craniopharyngioma.^23,26,53 Growth hormone deficiency is the most frequently observed deficit, with more than 75% of patients being affected. Specific hormonal deficiencies are identified, with luteinizing hormone/follicle-stimulating hormone (40% of patients) more commonly affected than adrenocorticotropic hormone (25%) and thyroid-stimulating hormone (25%).⁵⁴ Diabetes insipidus is reported in up to 17% of children and 30% of adults.

Hydrocephalus is an important concomitant factor, particularly in pediatric craniopharyngioma. Hydrocephalus is identified at diagnosis in approximately a third of craniopharyngioma patients overall and in almost one third of children with craniopharyngioma^36,54–56 and may require definitive treatment if primary tumor surgery fails to resolve the issue. In one series, 43% of children went on to require long-term treatment of hydrocephalus.⁵⁶ In another series, only 29% of adult patients had any evidence of hydrocephalus at initial evaluation, although there was a greater than 50% incidence of hydrocephalus in the pediatric population.⁴⁸ Adequate treatment of hydrocephalus is imperative to minimize long-term cognitive deficits in these children, especially in those undergoing radiation therapy. There would seem to be a correlation between shunt requirement and worse outcome; however, it remains to be clarified whether this is directly related to shunting or is due to the presence of generally larger tumors with hypothalamic involvement in this group.⁵⁴

Neurobehavioral abnormalities appear to be more common in adults than in children. It has been estimated that more than 30% of adult patients with craniopharyngioma older than 45 years have dementia or suffer from intermittent confusion, hypersomnia, apathy, or depression.^57,58 Children may also suffer from neurocognitive decline and exhibit common clinical features such as abulia, psychomotor retardation, and flattening of affect.

Adults are less often afflicted with the hypothalamic regulatory symptoms encountered in children. Central hyperphagia with obesity, disturbances of thirst, and alterations in sleep cycles are disorders that seem to predominantly involve the pediatric population.

Very rarely, craniopharyngioma may develop acutely after intratumoral hemorrhage⁵⁹ and rarely may rupture and result in aseptic meningitis or spontaneous drainage through the nasopharynx.^60–62

There is considerable difficulty in diagnosing craniopharyngioma in young children because some may have relatively nonspecific symptoms such as vomiting and irritability, and visual field loss is often overlooked. A high degree of clinical suspicion is needed in such cases. It has been recognized that the diagnosis of brain tumors in children is frequently delayed in comparison to other childhood tumors.^63–65

Pathology

In 2007, the World Health Organization (WHO) grading system for craniopharyngioma defined two major subtypes of the tumor, adamantinomatous and papillary, with both corresponding to WHO grade I.⁶⁶ Transitional or mixed forms have also been described but are rare.^30,67 The classic adamantinomatous type appears to be present in more than 95% of pediatric cases.⁵⁵ It is distinctly uncommon for children to display the papillary squamous subtype in isolation or mixed with adamantinomatous histology. The papillary squamous variant is almost exclusively seen in adults and represents close to 30% of all craniopharyngiomas seen in this population.^30,55

Typically, adamantinomatous craniopharyngioma is a lobulated cystic and solid mass. The cysts classically contain fluid of variable composition that may be brown or green, the so-called crankcase oil. Classically, in this subtype there are secondary changes such as calcification, fibrosis, and the presence of cholesterol-rich deposits. They may superficially involve brain tissue and be adherent to adjacent vascular and neural elements.

Histologically, adamantinomatous craniopharyngioma is composed of squamous epithelium in cords, lobules, and trabeculae surrounded by palisaded columnar epithelium.⁶⁸ “Wet keratin” nodules may be found within the solid portion of the tumor, and a gliotic reaction with abundant Rosenthal fibers is often seen in adjacent brain tissue (Fig. 135-1).

FIGURE 135-1 A, Adamantinomatous craniopharyngioma. The epithelium has a prominent peripheral palisading growth pattern (long arrow), looser stellate reticulum (short arrow), and calcifying “wet” keratin (arrowhead). This lesion is surrounded by gliotic brain tissue (lower right corner) (hematoxylin-eosin, ×250). B, Papillary craniopharyngioma. Transitional-type epithelium has papillary vascular cores (arrow), exfoliating squames, and “dry” keratin (arrowhead) (hematoxylin-eosin, ×250).

The typical papillary subtype has a well-circumscribed solid appearance with a lower likelihood of cysts and absence of calcification and cholesterol deposits. Histologically, the papillary subtype is a bland mass of well-differentiated squamous epithelium forming pseudopapillae with an anastomosing fibrovascular stroma.^30,31,55

Electron microscopy is rarely needed for the diagnosis of craniopharyngioma but typically reveals glycogen and tonofilaments in epithelial cells, which are joined by desmosomes.⁶⁹ Mineral precipitates are seen in membrane-bound vesicles. Immunohistochemistry is positive for cytokeratins⁷⁰ and epithelial membrane antigen.⁶⁸

Malignant transformation of craniopharyngioma has been discussed in the literature but is thought to be very rare and may require additional oncogenic insults, such as exposure to radiation.^71–73 The molecular genetic abnormalities associated with craniopharyngioma remain poorly characterized, although there are several reports of clustering of craniopharyngioma in families suggestive of a putative genetic basis.^74–76 Some craniopharyngiomas are monoclonal in origin,^77,78 and cytogenetic abnormalities have been reported in chromosomes 2 and 12,^77,79,80 but additional studies have not shown significant chromosomal imbalances in either type of craniopharyngioma.^81,82

Evidence is emerging that implicates specific genes and cell signaling pathways in the development of craniopharyngioma. Mutations of the β-catenin gene have been identified in 70% of adamantinomatous craniopharyngiomas,^83,84 whereas none were seen in papillary craniopharyngiomas. β-Catenin is a downstream component of the Wnt intracellular signaling pathway involved in proliferation, morphogenesis, and differentiation,⁸³ and it has been postulated that disruption of this pathway may be important in the pathogenesis of adamantinomatous craniopharyngioma.

Natural History

Information regarding the natural history of craniopharyngioma is sparse because most patients eventually undergo treatment. In an Oxford (U.K.) series, 13 patients did not initially receive treatment, and 92% of them ultimately required treatment for evidence of disease progression during the study period.³⁶

Neuroimaging

Plain radiography of the skull is now rarely performed in patients suspected of having a craniopharyngioma; however, radiographs may provide information regarding the size and shape of the sella and may demonstrate lesional calcification. Approximately 65% of adults and 90% of children with craniopharyngiomas will have abnormal findings on skull radiographs. Calcification of the tumor is seen in approximately 40% of adults and 85% of children.⁸⁵ Calcification is not a unique feature of adamantinomatous lesions inasmuch as it has been demonstrated in histologically confirmed papillary tumors.^30,55

Classically, the diagnosis is made with computed tomography (CT) and magnetic resonance imaging (MRI). These techniques allow the neurosurgeon to categorize the lesion in terms of its anatomic position and to appreciate the relationship of the tumor to the pituitary gland, optic apparatus, third ventricle, and major intracranial vessels. CT will reveal a mass located within the suprasellar region or, less commonly, in an intrasellar or parasellar location. CT images of the tumor frequently contain areas of mixed attenuation corresponding to cystic and solid areas, as well as hyperdense regions typical of calcification, which is reported in 45% to 57% of subjects overall and in 78% to 100% of children. When contrast-enhanced imaging is performed, the solid component and the cystic capsule of the tumor are seen to be well demarcated. Obstructive hydrocephalus is a possible accompanying feature of large tumors.

Today, MRI is more commonly used to fully characterize a craniopharyngioma. Classically, the solid tumor is isointense to hypointense on T1-weighted images, and T2-weighted images show mixed hypointensity or hyperintensity; reticular enhancement is seen after the injection of gadolinium.⁸⁶ Edema may be identified in adjacent brain tissue or along the optic tract and is useful in differentiating craniopharyngioma from other tumors in this region.⁸⁷

In a series of 86 adult patients with craniopharyngiomas at the University of Erlangen, 80% of the tumors were heterogeneous in appearance.⁵¹ Most of the tumors were either monocystic with a solid component or predominantly solid with a cystic component. A minority were entirely cystic or entirely solid. All these tumors were suprasellar, with 57% of them harboring an intrasellar component. In addition, 60% of the suprasellar tumors had a component that was retrosellar, and 40% had a component that was in either the posterior fossa or the parasellar space.

There are no radiologic features that can absolutely discriminate among the subtypes of craniopharyngioma. Yet lobulated shape, vessel encasement, and calcification have all been postulated to be indicative of the adamantinomatous subtype.^30,67,88

Classification and Grading Schemes

A number of classification schemes have been proposed to assist in decision making regarding surgery, particularly concerning the approach and its concomitant risks.^54,89–91 Hoffman and colleagues proposed intrasellar, prechiasmatic, and retrochiasmatic as three basic subtypes,¹⁵ whereas Samii and Bini devised a five-tier grading system based on vertical height of the tumor.⁹² Yasargil and associates recommended grading with respect to the diaphragma and the third ventricle (Fig. 135-2).⁵⁴ The most recently proposed grading system, from Puget and coworkers, relates to the degree of involvement of the hypothalamus to further define resectability (Fig. 135-3).⁹⁰ No one system has come into widespread use, but all have useful elements for approaching these tumors surgically, considering their position in relation to the chiasm, or taking into account their vertical height and hypothalamic involvement.

FIGURE 135-2 Diagrammatic representation of the most common locations of craniopharyngiomas. A, Purely intrasellar-infradiaphragmatic. B, Intrasellar and suprasellar, infradiaphragmatic and supradiaphragmatic. C, Supradiaphragmatic, parachiasmatic, extraventricular. D, Intraventricular and extraventricular. E, Paraventricular with respect to the third ventricle. F, Purely intraventricular.

(From Yasargil MG, Curcic M, Kis M, et al. Total removal of craniopharyngiomas. Approaches and long-term results in 144 patients. J Neurosurg. 1990;73:3-11.)

FIGURE 135-3 Preoperative (left column) and postoperative (right column) magnetic resonance imaging (MRI) classification of pediatric craniopharyngiomas. Upper left, grade 0, no hypothalamic involvement. Center left, grade 1, hypothalamus displaced by the tumor. Lower left, grade 2, hypothalamic involvement. Upper right, grade 0, no hypothalamic damage. Center right, grade 1, minimal hypothalamic damage. Lower right, grade 2, severe hypothalamic damage.

(From Puget S, Garnett M, Wray A, et al. Pediatric craniopharyngiomas: classification and treatment according to the degree of hypothalamic involvement. J Neurosurg. 2007;106(Suppl):3-12.)

Giant craniopharyngiomas have been defined as tumors that have a maximal diameter greater than 5 cm.⁹³ They are frequently cystic in nature and may extend into the anterior, middle, and posterior fossa.

Treatment

Many treatment options are available for craniopharyngioma, and many factors need to be considered when managing patients. Important factors include age; pubertal development; growth; the site, size, and consistency of the tumor; the presence of hydrocephalus; the ability and experience of the surgeon; and the availability of radiation and intracavitary treatment.

On diagnosis of a craniopharyngioma, any immediate threats to the patient’s life need to be dealt with urgently. Up to 50% of children will have obstructive hydrocephalus that may warrant rapid ventricular drainage. If the patient is severely obtunded as a result of hydrocephalus, urgent external drainage should be performed. Most authors would advocate treatment of the hydrocephalus with an external drain or cyst aspiration, or both, before attempting resection to allow stabilization of the patient’s clinical state. In general, shunting is avoided at initial encounter but may certainly be required later in the course of the illness.

Full endocrinologic assessment is required, and appropriate replacement therapy should be provided, with particular emphasis on identifying diabetes insipidus and hypocortisolemia. An estimate of bone age and, in young women, ovarian ultrasonography are advocated.⁹⁴ Likewise, accurate neuro-ophthalmologic assessment, including visual field testing, is critical to have a thorough understanding of the tumor and its relationship to the visual apparatus and as a baseline for analysis after treatment.

Traditionally, surgical resection has been the preferred first option for treatment of these lesions. Most would recommend that if complete surgical resection can be performed without injury to the anterior hypothalamus and without effect on personality and quality of life, it should be performed. The difficulty lies in achieving this goal in a high percentage of cases. An increasing number of experts advocate subtotal resection because of its lower perioperative complication rate, supplemented by adjuvant radiotherapy.^56,90,95 Such management has been shown to be associated with equivalent cognitive outcomes and less neurological impairment and deterioration of quality of life.

At some institutions, radiotherapy and even intracavitary therapy are used as first-line treatment. Unfortunately, because of the rarity of the disease and the complexity added by significant variations in tumor size, location, and multimodality treatment, evidence of the most appropriate treatment of craniopharyngioma is still lacking.

All available therapies are addressed here, with an emphasis on surgical strategies, both attempted gross-total resection (GTR) and subtotal excision.

Surgical Therapy

Complete surgical resection appears to be an important prognostic factor for recurrence and is the best management method for craniopharyngioma if it can be done safely. It requires great surgical skill and judgment, but considerable effort should be exerted to perform as complete a resection as safely possible. Unfortunately, complete resection may be very difficult to achieve.⁹⁶

The most appropriate surgical corridor for resecting a craniopharyngioma is determined by numerous factors, including the shape and size of tumor, the presence of cysts, its location, the degree of calcification, and the surgeon’s preference and experience (Fig. 135-4). The standard approaches for attempted GTR include pterional, orbitozygomatic, subfrontal/trans–lamina terminalis, interhemispheric-transcallosal, and transcortical-transventricular; reports of endoscopic endonasal transsphenoidal removal of craniopharyngiomas are emerging as well.

FIGURE 135-4 Surgical corridors that may be useful for the approach to a craniopharyngioma, depending on the size and pattern of the tumor and preference of the surgeon.

Gross-Total Resection

Subfrontal/Trans–Lamina Terminalis Approach

Suitability

This approach is most favored in the presence of a midline prechiasmatic tumor that extends into the anterior cranial fossa floor or superiorly into the suprasellar cistern and the third ventricle.⁹⁷ Its advantages include the midline orientation of the approach with access to both the optic nerves and internal carotid arteries, as well as the third ventricle via the lamina terminalis.

Operative Details

The patient is placed in a supine position with the head slightly extended such that the anterior skull base is perpendicular to the floor. Head fixation is preferred, and the use of neuronavigation equipment may be helpful, particularly for solid tumors. A lumbar drain may be considered. Mannitol and dexamethasone are administered. A bicoronal incision is made, with preservation of a vascularized pericranial graft for use in reconstruction if necessary. Once adequate bony exposure has been achieved, a low unilateral or bilateral frontal craniotomy is performed, and if present (in older children and adults), the frontal sinus is opened. In general, we prefer a unilateral craniotomy to avoid bihemispheric injury. Cranialization may need to be performed on the frontal sinus. Additional removal of the orbital bar may provide greater exposure.⁹⁸ The dural opening is created behind the orbital bar, and the right olfactory nerve will usually be dissected from the undersurface of the frontal lobe or divided. Elevation of the frontal lobes from the anterior cranial fossa floor may be added by dividing the superior sagittal sinus at the floor. Exposure of the optic nerves, optic chiasm, and carotid arteries bilaterally is then afforded. Opening of the lamina terminalis immediately posterior to the chiasm then allows access to tumors that extend into the third ventricle.

Difficulties

Both frontal lobes are elevated during the bifrontal approach, which may be associated with increased postoperative morbidity. This approach is also compromised by the potential for injury or the necessity for sacrifice of one of the olfactory nerves. The frontal sinus will be opened when present (in older children and adults) and will require cranialization; there is a risk for infection or CSF leakage with this procedure. Removal of an intrasellar tumor can be difficult when using a subfrontal approach, but it is possible and may be facilitated by the use of an angled endoscope (Fig. 135-5).

FIGURE 135-5 Demonstration of the subfrontal approach through the lamina terminalis, which is used for most suprasellar craniopharyngiomas.

Bifrontal Basal Interhemispheric Approach

Suitability

Although the subfrontal approach is favored by many neurosurgeons, the basal bifrontal interhemispheric approach has been proposed by others.⁹⁹ This approach is well suited for large, midline, retrochiasmatic tumors that may have retrosellar extension. Although it may be more technically challenging, this approach allows wider visualization of the optic pathway and anterior circle of Willis. Proponents of the bifrontal basal interhemispheric approach cite its ability to avoid the potential blind spots encountered with unilateral approaches. This technique has also been combined with division of the anterior communicating artery in an effort to maximize removal of the retrochiasmatic portion of these tumors.⁹⁹

Operative Details

With this approach a bifrontal craniotomy flush with the anterior skull base is crucial to avoid significant brain retraction. Removal of the supraorbital bar may also be incorporated with the craniotomy in a single or separate step to maximize bony exposure. Once the olfactory tracts are dissected from the brain surface, the chiasmatic and interhemispheric cisterns are opened so that the optic chiasm, bilateral A2 segments of the anterior cerebral artery, and anterior communicating vessels are well visualized. After opening the lamina terminalis, the tumor is internally decompressed. The challenge of removing the tumor capsule from the vessels and neural structures is often the limiting factor, as in any approach.

Difficulties

The utility of the bifrontal basal interhemispheric approach is tempered by the recognition that division of the bilateral anterior bridging veins, combined with frontal lobe retraction, increases the potential for bilateral frontal lobe injury.

Transsphenoidal and Extended Transsphenoidal Approaches

Suitability

Smaller midline tumors within the sella or with an infradiaphragmatic suprasellar component may be removed by the transsphenoidal route. This route is most favorable for patients with enlargement of the sella. Significant suprasellar extension of craniopharyngiomas can be difficult to access from a transsphenoidal approach; however, the presence of cystic rather than solid disease makes its use more favorable.¹⁰⁰ Advantages of this approach include the lack of need for brain retraction and potentially better visual outcomes than observed when using cranial approaches.^54,101,102

Operative Details

The patient is placed supine on the operating table with the head elevated and slightly angled toward the surgeon. Use of a Mayfield headrest and neuronavigation devices can obviate the need for fluoroscopy, although either or both can be used. The procedure can be performed with an endonasal endoscope¹⁰³ or by using the operating microscope with a nasal speculum. Sublabial, transseptal, and direct approaches to the sphenoid face have all been described. The mucosa is reflected, and the sphenoid sinus is opened with a drill or Kerrison punch. The mucosa of the sinus is excised, and the anterior wall of the sella is removed to expose the sella dura. Anterior compression of the anterior pituitary is a common finding, and the gland may need to be divided to provide access to the tumor.¹⁰⁴

For the extended transsphenoidal procedure, the tuberculum sellae can be removed, and additionally, excision of the planum sphenoidale will provide improved access to the suprasellar region. The dura may then be opened over the gland and the circular sinus and anterior to the sella to provide access to the suprasellar cistern. The dural defect is closed with a graft and supported by bone or synthetic plates, with fat placed in the sphenoid and a vascularized nasal flap added for coverage of the site of surgical access from the nasopharynx.¹⁰⁵ Some authors advocate the use of postoperative lumbar drainage to reduce the risk for delayed CSF rhinorrhea.¹⁰⁶

Difficulties

Lateral extension of the tumor can be difficult to access from this approach, as can large tumors. Tumor involvement in the region of the anterior cerebral complex may expose the perforating vessels to risk for injury during surgery. Direct control of intracranial neural and vascular structures is inferior when using the transsphenoidal or extended transsphenoidal approach (Fig. 135-6). Suprasellar calcifications are thought to be a contraindication to the use of this approach.¹⁰⁴ This approach can be difficult or impossible to use in children with a poorly pneumatized sinus and in patients with nasal and sinus pathology. Reconstruction after tumor removal can be complicated, and high rates of CSF leakage have been reported in the literature, a problem that has not been completely resolved after extended transsphenoidal surgery. Use of a vascularized nasal mucosal flap is showing promise in this regard.¹⁰⁵

FIGURE 135-6 The transsphenoidal approach is useful primarily if the sella is enlarged and the tumor is cystic.

Pterional Approach

Suitability

The pterional approach has traditionally been the most favored one for resection of craniopharyngiomas,^54,90,96 and it would seem to best be suited for smaller tumors confined to the suprasellar space.⁹⁸ It does allow access to both prechiasmatic and retrochiasmatic lesions, along with those above and below the diaphragma, and may be used in combination with interhemispheric-transcallosal or transcortical-transventricular approaches to remove larger lesions with significant suprasellar extension.

Operative Details

The patient is positioned supine on the operating table with the head turned and elevated such that the malar eminence is uppermost. A frontotemporal incision is made, and the temporalis muscle can be raised with the skin as a myocutaneous flap or reflected posteriorly after interfascial dissection. A frontotemporal bone flap is elevated, and the lateral aspect of the lesser wing of the sphenoid is drilled away. Frontal extension of the craniotomy is advocated by some authors to improve access. The dura is opened and reflected anteriorly. The sylvian fissure is split, and frontal and temporal retractors may be used judiciously to provide access to the tumor. Extension of craniopharyngioma into the third ventricle may be removed by opening the lamina terminalis.

Difficulties

Difficulties primarily relate to visualization of the opposite carotid artery and access to the third ventricle. Brain retraction may be necessary. In the case of large retrochiasmatic or retrosellar lesions, the pterional approach offers a narrow window that may be obstructed by perforating vessels.

Orbitozygomatic Approach

Suitability

The orbitozygomatic approach is essentially an extension of the pterional approach, with removal of the lateral orbital bar and zygoma. It affords greater access to tumors with significant suprasellar extension.

Operative Details

The patient is placed supine on the operating table with the head turned 30 to 45 degrees and elevated 30 degrees in a Mayfield headrest. A frontotemporal incision is made, followed by interfascial dissection to reflect the temporalis inferoposteriorly. The frontotemporal craniotomy is extended to involve the lateral orbital bar and zygoma. The dural opening and intradural procedure is then similar to the pterional approach but is extended to allow access to lesions with more vertical height.

Difficulties

There is more soft tissue dissection involved in the orbitozygomatic approach, and reconstruction of the zygoma can be associated with poor cosmesis.

Interhemispheric-Transcallosal Approach

Suitability

Large midline tumors with suprasellar extension into the third and, potentially, the lateral ventricle can be removed if the interhemispheric-transcallosal approach is combined with a basal procedure. It may be satisfactorily used alone in the rare setting (3% to 10%) of a purely third ventricular craniopharygioma.⁵⁴

Operative Details

The patient is placed supine in a Mayfield headrest with the head elevated 30 degrees and the neck flexed. A linear or U-shaped flap incision can be made anterior to the coronal suture. A craniotomy is performed that is predominantly over the nondominant hemisphere but with exposure of the sagittal sinus at approximately two thirds of its length anterior and one third of its length posterior to the coronal suture, although this location may be modified after use of a neuronavigation system. The dura is reflected toward the sinus while taking great care to preserve cortical venous drainage. The ipsilateral hemisphere is gently retracted to allow dissection in the interhemispheric space down to the callosum. Care is taken to identify and preserve the pericallosal arteries on the corpus callosum. A 1.5- to 2-cm incision is made in the corpus callosum, and the lateral ventricle is entered. Tumor may be resected through an enlarged foramen of Monro, or the choroidal fissure can be opened to allow greater access to the third ventricle. Alternatively, an interforniceal approach with direct access to the third ventricle can be used. Internal decompression with piecemeal extirpation of tumor is favored in this location.

Difficulties

The interhemispheric-transcallosal approach is generally used in combination with a subfrontal or pterional procedure. This approach puts at risk the medial hemisphere from retraction, in addition to the pericallosal arteries and fornix, as well as the veins and floor of the third ventricle.

Transcortical-Transventricular Approach

Suitability

The transcortical-transventricular approach is rarely performed for resection of craniopharyngiomas. A candidate for this approach, generally in combination with a basal approach, would be a patient with hydrocephalus and craniopharyngioma extending into the third ventricle, particularly through the foramen of Monro.

Operative Details

The patient is placed supine on the operating table with the head elevated and in a Mayfield headrest. A linear or U-shaped flap incision is made to expose the frontal bone just anterior to the coronal suture. A neuronavigation system can be useful for planning the bone flap and to direct access to the ventricle. The dura is reflected medially and the corticectomy performed through the middle frontal gyrus. The lateral ventricle is entered, and the surgical corridor is secured with the use of a Greenberg (or similar) retractor. The tumor is identified and may be resected from the ventricle and followed through the foramen of Monro into the third ventricle.

Difficulties

The transcortical-transventricular approach involves cortical injury with an increased postoperative risk for seizures. The size of the ventricle is important, and hence in the absence of significant hydrocephalus, this approach is unfavorable. Ipsilateral dissection of the wall of the third ventricle is also difficult with this approach.⁵⁴

Results of Attempted Gross-Total Resection

Rates of radiologically confirmed GTR vary significantly in the microsurgical neurosurgery era. Yasargil and coauthors reported performing GTR in 90% of 144 surgical patients,⁵⁴ whereas Fahlbusch and others have reported rates closer to 50%,^53,90,96 and Karavitaki and associates documented 18% of 103 tumors as being completely resected.³⁶ Some authors have identified greater GTR rates in children (77%) than in adults (27%).⁵⁵ Large tumor size, supradiaphragmatic location, hydrocephalus, and recurrence are adverse prognostic factors for radical resection.^{13,53,55,96,107}

In addition to variation in achievement of gross-total control among series, there is significant variation in reported recurrence rates after GTR. The lowest rates document 0% recurrence after GTR at 10 years,³⁶ 15% at 10 years,⁹⁸ 19% at 10 years,⁹⁶ 17% at a mean follow-up of 49 months,⁵⁵ and 36% at a median follow-up of 7 years.⁹⁰ Additionally, other authors have reported higher rates, including a 43% recurrence rate after GTR at a median follow-up of 78 months.¹⁰⁸ In the Iowa series, local control rates after complete resection were reported to be 50%,¹⁰⁹ and in a Pittsburgh study, the local control rate at 10 years after surgery alone was 42%.¹¹⁰

Postoperative Mortality and Morbidity

Postoperative morbidity and mortality are central issues in the management of craniopharyngioma. Postoperative mortality in some early series was reported to be as high as 41%.^32,111–113 More recent series have reported mortality of 1.7% to 5.4%,^15,53,96 although a mortality rate of about 15% in the first postoperative year was reported in a group of adult patients undergoing aggressive microsurgical resection.⁵⁴

In general, radical excision has been associated with higher morbidity and mortality, but there are exceptions.^36,96 Mortality in adults is most often the result of hypothalamic damage or coexisting medical illness. Patients who undergo transsphenoidal resection consistently have lower overall mortality rates than do those who undergo craniotomy.^96,114

Visual decline after an aggressive surgical attempt occurs in 4% to 30% of patients.^15,51,54,55 Important variables predicting visual outcome appear to include the extent and duration of preoperative visual deficits, the relationship of the tumor to the optic apparatus, and performance of transsphenoidal versus transcranial surgery. In Yasargil and colleagues’ series of adult patients, all who had normal vision preoperatively retained normal visual acuity postoperatively.⁵⁴ In contrast, vision in 50% of patients with preoperative visual deficits either stabilized or declined postoperatively. Rates of visual decline in patients treated by subtotal resection followed by radiation therapy varied from 2% in most series to as high as 30% in some series.^115,116

One of the most common initial symptoms in adults with craniopharyngioma is endocrinopathy, but relatively few studies have methodically looked at preoperative and postoperative hormonal status in the adult population. In general, most studies state that surgical intervention leads to a significant degree of endocrine dysfunction.^15,54,117 The endocrine requirements of patients have been found to be greater after undergoing GTR than after subtotal resection or after subtotal resection plus radiation therapy,¹⁰⁸ in a manner similar to results that document visual impairment and hypothalamic obesity to be greater after undergoing GTR.

Deficiencies of four or more hormones develop in more than 75% of patients who undergo aggressive tumor resection.^52,118 Diabetes insipidus is seen postoperatively in about 80% of patients who undergo aggressive tumor removal, as opposed to 38% of those who undergo partial resection and 22% of those treated by radiotherapy alone.¹¹⁶ Other studies have claimed improvement in the patient’s endocrine status after transsphenoidal resection, as long as the pituitary stalk is left intact.¹¹⁹

One study examined the preoperative and postoperative endocrine status of 140 predominantly adult patients with craniopharyngiomas.¹²⁰ Preoperatively, approximately 75% of patients had evidence of growth hormone deficiency and secondary hypogonadism. Hyperprolactinemia, secondary adrenal failure, and hypothyroidism were found in 41%, 32%, and 25% of patients, respectively. Preoperatively, diabetes insipidus was relatively uncommon, being clinically evident in approximately 15% of patients. Postoperatively, diabetes insipidus was common, with an incidence of 59% at 3 months. This finding is consistent with the series of Yasargil and colleagues,⁵⁴ wherein permanent postoperative diabetes insipidus developed in 68% of patients. In general, it is rare to witness any improvement in endocrine status, and those with a partially deficient hypothalamic-pituitary axis frequently deteriorate.¹²⁰

Many proponents of limited surgery point to evidence that radical surgery has the potential to inflict significant neuropsychological damage. The majority of these data have been retrospective in nature and are derived from craniopharyngioma series made up predominantly of children. Up to a third of children exhibit impaired frontal lobe function postoperatively.^15,121 Studies including both adults and children that have controlled for age have suggested an association between the extent of tumor resection and Karnofsky Performance Scale (KPS) score. In one study it was found during follow-up that those who underwent GTR were more likely to have a KPS score in the 80 to 100 range.⁵⁵ Only one prospective study has been conducted that exclusively looked at neuropsychological outcome in adults.¹²² Within this small series of 13 patients, 10 underwent transcranial surgery in an attempt to achieve GTR. A battery of tests were used in this study, both preoperatively and postoperatively. No significant impairment in neuropsychological performance or quality of life could be demonstrated postoperatively.

Because of the potential adherence of craniopharyngiomas to blood vessels, postoperative vascular complications have also been reported. Fusiform dilation of the carotid artery is believed to result from possible adventitial damage that occurs when craniopharyngiomas are peeled off this vessel.^123,124 Although most of these cases involve pediatric patients, it can also occur in the adult population.⁵⁴ In addition to fusiform dilation, significant postoperative vasospasm resulting in permanent cerebral ischemia has been reported.¹⁵

Subtotal Resection

Subtotal resection of craniopharyngioma involves limited surgery to decompress cystic or solid components of the tumor to alleviate symptoms, restore vision, reestablish CSF flow, and reduce the volume of the radiation field. Subtotal resection can be considered to incorporate a range of procedures, from stereotactic or endoscopic cyst aspiration and biopsy, to open biopsy and decompression, to more aggressive resection of tumor without the aim of GTR, and to preservation of the infundibulum, hypothalamus, and brainstem. It has been proposed as an approach to reduce the morbidity of surgery for craniopharyngioma and, with the addition of adjuvant conformal irradiation, to maintain effective disease control.^56,95

Stereotactic Cyst Aspiration

In many instances, one encounters a craniopharyngioma that is mainly cystic in nature. These large cysts can be decompressed as either a primary or a definitive procedure. Frequently, this maneuver rapidly alleviates many of the symptoms of visual compromise, hypothalamic dysfunction, and increased intracranial pressure. It is often possible to pass a catheter through the ventricular system and into the cyst. The catheter is then connected to a reservoir system. Once the cyst is decompressed, the solid portion of the tumor is removed. Because most cysts reaccumulate within 2 months, definitive surgical resection is often done within 4 weeks of cyst decompression.⁹⁶ Another option is to repeatedly tap the reservoir when there is clinical or radiographic evidence of recurrence or to use this portal of entry for intracavitary radiotherapy or chemotherapy.

Recurrence and Patterns of Failure

Craniopharyngioma carries a significant risk for local recurrence and may rarely recur at a distant site, either as a result of direct implantation during surgery or by CSF dissemination.^181–184 Tumor recurrence in the intrasellar space in patients who have undergone transcranial procedures highlights the importance of adequate intrasellar exposure during transcranial operations.¹⁸⁵

The diagnosis of recurrence may be made by routine imaging, by reappearance of symptoms, or in more novel ways such as through screening assessment of urinary matrix metalloproteinase levels.¹⁸⁶

As discussed previously, the rate of recurrence of craniopharyngioma at 10 years after GTR (confirmed on postoperative MRI) ranges from 0% to 69%.^{36,53,55,96,187–189} An unresolved issue is exactly what surveillance protocol is optimal for patients with craniopharyngioma to maximize detection of recurrence without unduly wasting resources. Most recurrences seem to occur within the first 5 years after surgery, but delayed recurrence has been reported, and lifelong follow-up of most of these patients is advocated.⁹⁸ One suggested approach is to perform annual MRI after GTR, with studies at 6-month intervals if resection of the tumor was subtotal.¹⁰⁶

Sex

There is no evidence to suggest a difference in recurrence rates based on sex.^33,36

Radiotherapy

Studies comparing subtotal resection alone and resection combined with radiotherapy have demonstrated the ability of radiotherapy to increase the time to local tumor recurrence and to improve overall survival.^{33,36,85,156,200} The risk of recurrence for subtotally resected lesions treated with adjuvant radiation therapy is 15% to 30%.^28,33 Rajan and associates,³³ in a large retrospective study in which 55% of the patients were adults, examined the results of limited surgery combined with radiotherapy for the treatment of craniopharyngioma. Only 4 of the 173 patients in this series underwent complete resection, as reported by the surgeon. All patients in this series received radiotherapy. The progression-free survival rate was 83% at 10 years.

Miscellaneous Factors

Although age and extent of surgical resection are by far the most well investigated potentially prognostic factors, others have been suggested in the literature, including factors such as growth hormone administration. The location of the craniopharyngioma and its subsequent treatment result in a significant number of these patients being deficient in growth hormone (54% to 100%).^36,201,202 There is concern that patients receiving recombinant growth hormone may be at greater risk for recurrence of tumors and, by inference, for recurrence of craniopharyngioma based on in vitro, animal, and epidemiologic data in humans.^203–205 Most recent reports suggest that such is not likely to be the case.^206–209 In the Oxford series,²⁰⁸ 32 patients with a mean follow-up interval of longer than 10 years received growth hormone, whereas 53 patients with a mean follow-up of greater than 8 years did not receive it. During subsequent monitoring, tumor recurrence developed in 4 patients who received growth hormone and in 22 who did not. Multivariate analysis, however, did not show growth hormone administration to be a significant independent predictor of tumor recurrence.²⁰⁸

Treatment of Recurrence

If tumor recurrence has been identified after attempted GTR and radiotherapy has not been administered, the treatment options would consist of radiotherapy or reoperation followed by radiotherapy. Initial consideration can be given to reoperation in cases of local recurrence, although the likelihood of achieving GTR decreases to 0% to 25%,^36,53,96 and the mortality and morbidity related to second surgery have variably been documented to be higher in most series.^36,96 Mortality was nearly 10 times higher in the reoperation group than in the primary surgery group in Erlangen⁹⁶ and was 24% in the Oxford series.³⁶ Radiotherapy after re-resection has been documented to be beneficial, with 72% of patients remaining progression free at 10 years after radiotherapy, although this was not affected by whether the second surgery was performed.¹²⁶

If the recurrence is primarily cystic, intracystic therapies may be used, be it intracavitary irradiation^149,153 or chemotherapy with bleomycin or interferon, as described earlier.¹⁷³ If radiotherapy has already been administered, the treatment options become relatively limited in both scope and efficacy. Further radiation therapy was thought to no longer be feasible, but reports of the use of radiosurgery after irradiation are emerging.²¹⁰

Outcome

The overall survival expectancy for patients with craniopharyngioma is good, yet the lifelong morbidity associated with the disease remains unacceptably high.

Conclusion

Acknowledgements

We thank Dr. Rebecca Folkerth for her help in preparing the figures and the Brain Science Foundation for its support.