Craniopharyngiomas
Craniopharyngiomas constitute approximately 3% of all intracranial neoplasms.1,2 They are the most common nonglial tumor of childhood, accounting for 6 to 9% of pediatric brain tumors.3–7 Cushing8 graphically described craniopharyngiomas as “the kaleidoscopic tumors, solid and cystic which take their origin from epithelial rests ascribable to an imperfect closure of the hypophyseal or craniopharyngeal duct,” whose management is “one of the most baffling problems to the neurosurgeon.” The benign histology of these tumors is often in marked contrast to their malignant clinical course in children. The location of craniopharyngiomas, with their intimate association with the visual pathways, hypothalamus, and limbic system, predisposes patients with these tumors to severe visual, endocrine, and cognitive deficits, both at presentation and as a result of treatment. Although most children can compensate for neurologic deficits and endocrinologic deficiencies, the cognitive and psychosocial sequelae may be functionally devastating, interfering with education, limiting independence, and adversely affecting the quality of life as these children approach adulthood.9
Epidemiology
Although craniopharyngiomas comprise a significant proportion of pediatric brain tumors, on a population basis they are rare. Based on an analysis of three population-based cancer registries, the incidence of craniopharyngioma in the United States is between 0.13 and 0.18 per 100,000 per person-year.10 A bimodal distribution by age has been noted, with peak incidence rates in children and among older adults. In late adolescence and early adulthood (ages 15 to 34 years), the incidence is the lowest. Among children, the incidence is greatest between 6 and 10 years, followed by 11 to 15 years.10,11 Although some studies have reported that the majority of craniopharyngiomas occurred in children,12–14 the population-based registry data suggest that only 33 to 35% of all craniopharyngiomas occur in childhood.10 Based on these assumptions, 338 cases of craniopharyngiomas are expected to occur annually in the United States, with 96 occurring in children from 0 to 14 years of age.
Although there does not appear to be any racial or ethnic predilection for craniopharyngiomas, the influence of gender is unclear. Bunin et al10 describe an incidence that is nearly identical: 0.13 males and 0.12 females per 100,000 per year. There is also no gender difference in a population-based study from Finland.14 In contrast, clinical series have shown a mixed picture. A large hospital-based series of cases from the United Kingdom showed a ratio of 1.3 (107 males and 66 females),15 whereas in case series of craniopharyngiomas in children, the male/female ratios varied: 0.9 (42 tumors),16 1.2 (80 tumors),11 and 1.6 (105 tumors).17 Considering all the data, craniopharyngioma may occur slightly more often in boys.
Stiller and Nectoux18 have reported that the proportion of brain tumors that are craniopharyngioma varied substantially in different global regions: 1.5% in Australia, 4.7 to 7.9% in Europe, 3.9% in Japan, 2.7% in U.S. Caucasians, 4.9% in U.S. African Americans, and 11.6% in Africa.18 Although this international variation in occurrence has led to speculation regarding environmental influences, the data must be interpreted with caution. Because socioeconomic conditions preclude population-based reporting of all brain tumors in developing countries, variation in incidence is not a reliable statistic. Although percentages of reported tumor are more useful in comparing international rates because they will be less prejudiced by incomplete reporting, they are influenced by the proportions of other types of tumors, including those with nonspecific diagnoses such as brain tumor or malignant brain tumor. Although the frequency of craniopharyngioma appears increased in Africa and decreased in Australia, this conclusion is specious and not supported by clear data.10
Pathology
Craniopharyngiomas develop from epithelial nests that are embryonic remnants of Rathke′s pouch located along an axis extending from the sella turcica along the pituitary stalk to the hypothalamus and the floor of the third ventricle.2,19–21 Craniopharyngiomas gradually enlarge as partially calcified solid and cystic masses predominantly in the suprasellar region; the cystic component can reach several centimeters in size. They extend along the path of least resistance into the basal cisterns or can invaginate into the third ventricle. With continued growth superiorly into the third ventricle, hydrocephalus may develop.
Craniopharyngiomas have two basic patterns of cellular growth: adamantinomatous and papillary.1,2,12,22 Mixed tumors with both adamantinomatous and squamous papillary components or combinations of craniopharyngioma and Rathke′s cleft cysts can occur.1,2,12,22,23
The adamantinomatous tumors are the most common variant, occurring at all ages. They resemble the epithelium of tooth-forming tumors containing three distinct components: a basal layer of small cells; an intermediate layer of variable thickness with loose, stellate cells; and a top layer facing the cyst lumen where the cells are abruptly enlarged, flattened, and keratinized. At the cyst surface, desquamated epithelial cell are present either singly or in characteristic stacked clusters (keratin nodules). These nodules may undergo mineralization with accumulation of calcium salts, which in rare instances progress to metaplastic bone formation. The cysts in adamantinomatous craniopharyngiomas usually contain an oily liquid composed of these desquamated epithelia rich in cholesterol, keratin, and occasionally calcium.
Squamous papillary craniopharyngiomas occur nearly exclusively in adults and have a predilection to involve the third ventricle.24 They consist of solid epithelium, without loose stel-late zones, in a papillary architecture that resembles metaplastic respiratory epithelium.2,12,24,25 They are predominantly solid and rarely undergo mineralization. When cysts occur, the fluid is less oily and dark compared with their adamantinomatous counterparts. As a result of the absent calcification and limited cyst formation, complete curative surgical resection may be obtained more often than with adamantinomatous or mixed craniopharyngiomas.11,12,23 Histology, however, does not affect the risk of recurrence after subtotal resection or the response to radiation therapy.
Microscopic islets or “fingers” of adamantinomatous tumor embedded in densely gliotic parenchyma are frequently seen when the tumor arises in the region of the tuber cinereum, hypothalamus, and floor of the third ventricle.23,25–28 The gliotic reaction of Rosenthal fibers and fibrillary astrocytes, varying between several hundred micrometers and millimeters in thickness,28 effectively separates tumor from brain, thus providing a safe plane for surgical dissection.13,23,27,29,30 The presence of this gliotic tissue on surgical pathology is associated with a decreased risk of recurrence following a gross total tumor resection.23
Radiology
The role of neuroimaging is to establish a preoperative diagnosis and then define the location and extent of the cystic, solid, and calcified portions of the tumor and its relationship to the distorted normal anatomy. The radiographic evaluation includes computed tomography (CT), magnetic resonance imaging (MRI), magnetic resonance angiography (MRA), and, where available, magnetic resonance spectroscopy (MRS).31–34 Vascular anatomy can be well demonstrated by MRI and MRA, obviating the need for invasive cerebral angiography.31
Computed tomography and MRI have complementary roles in the diagnosis of craniopharyngiomas ( Fig. 19.1 ).31,34,35 CT is superior in the detection of the varied and complex calcifications, present in roughly 90% of craniopharyngiomas in children.13,31,36,37 The noncontrast CT usually demonstrates a suprasellar and often intrasellar mass with calcifications as well as hypodense solid and cyst components. The low density is usually greater than the attenuation of cerebrospinal fluid (CSF). A small percentage of craniopharyngiomas may be of high density.34 CT shows secondary changes in the skull base such as enlargement of the sella turcica and erosion of the dorsum sella.
Magnetic resonance imaging and MRA provide valuable information about the relationships of the tumor to surrounding structures, delineating the involvement or displacement of the visual pathways, hypothalamus, ventricles, and vessels of the circle of Willis. Noncontrast sagittal T1-weighted images may show the normal pituitary, facilitating the correct diagnosis.35 Fine calcifications may not be visible, or they may demonstrate a paradoxical increased signal on T1 imaging, or, if more substantial, they may exhibit characteristic signal voids. Craniopharyngioma cysts are uniformly bright on T2-weighted sequences; however, on T1-weighted sequences, the signal intensity of the fluid may range from hypointense to hyperintense, reflecting the heterogeneous contents.31,34 The correlation between MRI and the biochemical composition of cyst fluid is complex, with protein, lipid, and iron concentrations having a major influence on cyst signals.31,38 Cyst capsule and solid tumor vividly enhance with contrast.
Noncalcified solid craniopharyngiomas may have CT and MRI characteristics that are indistinguishable from those of other pediatric suprasellar neoplasms including chiasmatic hypothalamic gliomas, germinomas, and pituitary adenomas. Proton MRS demonstrates unique spectroscopic profiles that differentiate these tumors.33 Craniopharyngiomas show a dominant peak consistent with lactate or lipids and only trace amount of other metabolites. In contrast, gliomas demonstrate choline, N-acetylaspartate, and creatine with an increased ratio of choline to N-acetylaspartate compared with normal brain, and pituitary adenomas show choline peaks or no metabolites at all.
The surgeon′s impression of the extent of tumor resection must be confirmed by neuroimaging. Postoperative imaging with both enhanced MRI and CT is best done within 48 hours to avoid the artifacts of surgical trauma.31 Residual tumor should be graded according to the method of Hoffman30: grade 1, no residual tumor or calcification; grade 2, tiny (< 1 mm) fleck of calcification without evidence of enhancement or mass; grade 3, small “calcific chunk” without enhancement or mass effect; grade 4, small contrast-enhancing lesion without significant mass effect; and grade 5, contrast-enhancing mass. Although this grading scale has not been validated by large series, there is some evidence that small flecks of residual calcification on CT without solid or enhancing tumor on postoperative MRI may not portend an increased risk of tumor recurrence and should not be considered or treated as residual tumor.36
Clinical Presentation
Presenting signs and symptoms of craniopharyngiomas are related to pressure upon adjacent neural structures. The main presenting symptoms are raised intracranial pressure and headache in 60 to 75% of cases, and visual disturbances in approximately half of the children.35 Hypothalamic and endocrine dysfunction including growth failure (short stature), delayed sexual maturation, excessive weight gain, and diabetes insipidus are present in 20 to 50% of children at diagnosis but are less commonly the symptom that brings the child to medical attention. The prodrome usually occurs at less than 2 years of age.83
Formal preoperative neuro-ophthalmologic, endocrinologic, and neuropsychological assessment is mandatory. Seventy percent to 80% of children demonstrate abnormal visual acuity or fields on preoperative testing.35,83 The specific ophthalmologic deficits reflect the direction of growth of the tumor and its compression of various portions of the visual apparatus: prechiasmatic extension will compress optic nerves with loss of visual acuity, whereas posterior tumors cause chiasmatic compression with complex visual field defects. Endocrine evaluation shows growth hormone deficiency or gonadotropin deficiency in up to 60%, and thyroid or adrenal dysfunction in approximately one third.35 Less than 30% of children are endocrinologically normal at diagnosis.
Surgery
Operative Planning
Categorization of the pattern and extent of growth assists in evaluating treatment options and potential surgical approaches, and in predicting the outcome. Several different clinicoradiological classification systems have been proposed11,30,39–42; all attempt to describe the degree of vertical and horizontal extension, the displacement of the optic nerves and chiasm, the number of anatomic regions involved by tumor, and the overall size. The tumors may be entirely within the sellar or intra- and extrasellar subdiaphragmatic (Yasargil types a and b, Samii grades I and II, Hoffman sellar group, Choux group A); suprasellar and supradiaphragmatic, extending anteriorly to displace the optic nerves and chiasm posteriorly (Yasargil type c, Samii grades III to V, Hoffman prechiasmatic, Choux group B); suprasellar and supradiaphragmatic with tumor extending posterior to the chiasm, displacing chiasm and optic nerves forward and invaginating into the hypothalamus, mamillary bodies, basilar artery, third ventricle and brainstem (Yasargil types d and e, Samii grades III to V, Hoffman retrochiasmatic, add Choux group B); and purely intraventricular tumors (Yasargil type e, Choux group C).
Other anatomic grading scales have been shown to predict pre- and postoperative hypothalamic dysfunction.40,41 De Vile and colleagues40 created a scale that assesses the following variables to help determine the morbidity of subtotal or total resection: presence of preoperative hypothalamic disturbance, tumor height, and involvement of the hypothalamus. The authors correlated these preoperative variables and the intra-operative findings of adherence to the hypothalamus with postoperative hypothalamic dysfunction and imaging findings after surgery. They recommend that the planned radicality of surgery be dependent on the preoperative assessment of hypothalamic morbidity; they advocate total excision for patients with no imaging or clinical risk factors at presentation for hypothalamic injury, and limited resection for those with a high-risk profile. A similar assessment and recommendation for treatment strategy has been proposed by Puget et al,41 and they have used it prospectively to guide treatment of 22 children. They reported a marked decrease in hypothalamic morbidity after using their assessment scale to determine the surgical plan.
The size is graded as small (≤ 2 cm), medium (> 2 to 4 cm), large (> 4 to 6 cm), and giant (> 6 cm).11 Other authors use the “giant” label for a size of 5 cm or greater.41,43,44 Giant tumors may extend into multiple or all compartments, extending from the medulla to the foramen of Monro ( Fig. 19.2 ). In agreement with our results, other centers have reported higher morbidity, a lower chance of complete resection, and worse overall and progression-free survival with giant tumors.11,40,45,46 However, we found these differences were more apparent in children with recurrent tumors of giant size, where dissection planes are obscured, and less so with primary giant tumors.44
Debate persists about the optimal treatment of craniopharyngiomas in children. Some authors advocate radical resection for surgical cure,4,11,13,23,45,47–55 some recommend attempted radical resection only if hypothalamic injury is acceptably low,37,40,41,56–62 some recommend resection for solid tumors and intracystic chemotherapy for cystic tumors,63 and some recommend limited resection plus adjuvant radiation therapy (RT).6,64–68 The two major paradigms of surgical resection for cure and limited resection plus RT offer similar rates of overall and disease-free survival, with rates of recurrence between 20% and 30% in most large series.
Although even less consensus exists regarding treatment of recurrent craniopharyngiomas, some groups advocate repeat radical resection,13,39,48,49,55,69–71 whereas others prefer salvage radiation therapy.54,72,73 In our experience of 86 children with craniopharyngiomas, complete resection was possible in all 57 children with primary tumors and in 62% of recurrent tumors. The surgical risks were not, in fact, higher at reoperation, but the chance of complete extirpation was lower, especially in the setting of prior RT. Recurrence occurred in 20% of patients who had complete resection, but repeat surgery alone was successful in almost 80% of children. We believe surgical resection at centers of excellence offers the best chance of disease control and possible cure at both presentation and recurrence.
Operative Technique
A variety of operative approaches have been described and championed by different surgeons including the subfrontal,4,13,27 pterional,11,29,37,74 bifrontal interhemispheric,75,76 subtemporal,77 transcallosal,78 transpetrosal,79 and transsphenoidal approaches.80–84 Surgical adjuncts including the ultrasonic aspirator, frameless stereotaxy, and rigid and flexible neuroendoscopes should be available and utilized when appropriate.
The author prefers the pterional craniotomy as advocated by Yasargil.11 This approach offers the shortest, most direct route to the suprasellar region and, with wide splitting of the sylvian fissure, minimizes or eliminates retraction of normal brain. Tumors extending from the pontomedullary junction ( Fig. 19.3 ) to above the foramen of Monro can be removed through the pterional approach. In no patient is a cortical resection85 or sacrifice of the olfactory nerve30 necessary.
Dexamethasone (0.1 mg/kg), phenytoin (15 mg/kg), and cephalexin (25 mg/kg) are administered after induction and intubation. Mannitol (0.25 g/kg) is then given at the time of the skin incision to help maximize brain relaxation. The diuretic effect is maximal within the first hour of surgery, long before the requisite manipulation of the pituitary stalk and the hypothalamus, which may produce diabetes insipidus that complicates fluid and electrolyte management. A 7-cm frontotemporal craniotomy is performed with removal of the sphenoid wing; when necessary, the orbital rim can be removed with the craniotomy flap to obtain a wider operative corridor and shorter distance to the tumor. Prior to opening the dura, either intraoperative ultrasound or frameless stereotaxy is used to determine the location and extent of the tumor and its relationship to the operative exposure.
Throughout the surgery retraction of the brain is minimized. Mannitol, hyperventilation, and gradual drainage of CSF through the opened sylvian fissure and basal cisterns will usually provide excellent relaxation, even in the presence of moderate degrees of hydrocephalus. Ventricular drainage is reserved for cases refractory to these maneuvers or when the use of an intraventricular endoscope is anticipated (vide infra). Although hydrocephalus is present in 15 to 66% of patients,11,29,37,39,40,75 preoperative shunting is reserved for patients with severe symptoms of increased intracranial pressure that is unresponsive to medical management.
Because these tumors often extend diffusely throughout the suprasellar cisterns, displacing and distorting normal structures, identification of the vascular anatomy provides essential landmarks. Starting laterally, the sylvian fissure is widely split and the distal branches of the middle cerebral artery are identified. The arachnoidal dissection proceeds medially to the main trunk of the middle cerebral artery, which is followed proximally to the ipsilateral carotid bifurcation, anterior cerebral artery, and internal carotid artery. As the carotid is followed proximally to the clinoid, the optic nerve, chiasm, and tracts are identified in relation to the tumor.
Premature decompression of craniopharyngiomas, especially cystic tumors, causes the tumor capsule and arachnoid to become redundant, obscuring the planes of dissection. Working in the prechiasmatic, opticocarotid, and carotidotentorial triangles, an arachnoidal plane is developed and maintained between the intact tumor and the branches of the ipsilateral carotid and vessels of the circle of Willis, preserving all of the vessels and their perforating branches. This plane is developed posteriorly until the basilar artery is identified. In primary tumors, the membrane of Liliequist invariably separates the tumor from the basilar artery and serves as a posterior landmark.
Once the vascular anatomy has been identified and separated from the tumor, the cyst is aspirated and the solid internal component debulked. Care is taken to preserve the capsule of the tumor. The authors prefer inserting a 23-gauge needle into the cyst and removing cyst fluid. The hole is then closed with gentle bipolar coagulation. Again working in the parachiasmal spaces and maintaining arachnoidal planes, the tumor is progressively dissected free from the optic nerves, the contralateral carotid and its branches, and the inferior aspect of the optic chiasm. An attempt is always made to identify and preserve the pituitary stalk; this can be accomplished in 30% of patients. When the stalk cannot be separated free from the tumor, it is sectioned as distal as possible to prevent undue traction on the hypothalamus. After the tumor is dissected free from the entire circle of Willis, the pituitary stalk, and the optic apparatus, the capsule is grasped and, with continuous traction and blunt dissection, the gliotic plane is developed, which allows the tumor to be delivered from its attachment to the hypothalamus in the region of the tuber cinereum. After the tumor is removed, the entire bed must be inspected for inadvertent residual disease. A micromirror or angled endoscope is used to view the under-surface of the chiasm and hypothalamus to confirm a complete resection.
If the tumor extends into the third ventricle or has a significant retrochiasmatic component, the lamina terminalis is fenestrated. The lamina terminalis is easily distinguished from the chiasm, appearing pale or translucent, avascular, and often distended by tumor. As retrochiasmatic tumor is removed, the prechiasmatic space may widen, allowing an additional avenue for dissection.
A third ventricular tumor is simultaneously delivered through the lamina terminalis as well as from below the chiasm. Placement of a 2.3-mm neuroendoscope into the lateral or third ventricle assists in monitoring the delivery of the intraventricular component of the tumor. With the endoscope, simultaneous or sequential transcallosal exposure of the intraventricular tumor is usually not obligatory.
When the tumor extends into the sella turcica, removal of the posterior planum sphenoidale and tuberculum sellae may be required to gain adequate intrasellar exposure. After removal of tumor, any defects communicating with the sphenoid sinus must be obliterated with fat and pericranial grafts. For tumors with significant and tenacious intrasellar components, we have had success with staged transcranial followed by delayed transsphenoidal surgery.
Transsphenoidal Surgery
Although most craniopharyngiomas of childhood arise in the region of the tuber cinereum, a small percentage originates from more caudal craniopharyngeal duct cell rests within the sella turcica.83 As these tumors grow, the diaphragma sellae stretches over the dorsal aspect, separating it from suprasellar structures and preventing tumor adherence to the optic apparatus, hypothalamus, and vessels of the circle of Willis. This feature of the pathological anatomy allows a radical removal of infradiaphragmatic intrasellar tumors through a transsphenoidal approach.11,74,80,83,84,86,87 Early series estimated that somewhere between 3% and 15% of the tumors may be amenable to transsphenoidal resection.88 With the advancement of endoscopic techniques and extended transsphenoidal approaches, more centers are treating a greater proportion of craniopharyngiomas with infra- and supradiaphragmatic components and those entirely suprasellar in location.80,89–94
Transsphenoidal surgery in young children may present anatomic difficulties related to the small size of the bony structures, the narrow intranasal aperture between the turbinates, and the lack of a pneumatized sphenoid sinus. The presence of a conchal or prepneumatized sphenoid sinus is not a contraindication to transsphenoidal surgery; however, the bone must be meticulously drilled or chiseled under fluoroscopic control or image guidance to obtain wide access to the sella turcica.83,84,87,92 Other than the bony exposure, the technical aspects of the operation do not differ significantly from similar surgery in adults, particularly with regard to the overall approach and tumor re-section.37,81,83 However, the rarity of these tumors suggests that only surgical teams with adequate experience should utilize this approach.
After a wide dural opening, the normal ventrally displaced pituitary gland is encountered. The gland must be mobilized en bloc or incised in the midline and then gently pushed laterally to obtain exposure of the dorsally located craniopharyngioma.84,93 Once an initial plane of cleavage between the tumor and sellar wall is established, the capsule is opened with drainage of cyst fluid and debulking of solid neoplasm. Following this internal decompression, the capsule is dissected from the walls of the cavernous sinuses and pituitary gland to complete mobilization of the intrasellar tumor. When the superior capsule is adherent to the diaphragma, it must be incised and resected. As the superior craniopharyngioma is delivered, the remaining attachment of tumor to the pituitary stalk is visualized and detached with bipolar coagulation and sharp dissection to achieve a gross total resection. Resection of the diaphragma invariably produces an intraoperative CSF leak. Obliteration of the sella and sphenoid sinus with a free fat graft is mandatory. Several days of postoperative lumbar drainage is recommended.84
Total resection can be accomplished in 60 to 90% of primary infradiaphragmatic intrasellar craniopharyngiomas; however, the rate of success drops to 10 to 60% for recurrent tumors.74,80–82,84,92,95 In experienced hands, operative mortality ranges from 0 to 4% and nonendocrine morbidity occurs in 15 to 25% of patients, with children tending to do better than adults.37,74,80,81,83,84,87,92 The incidence of new diabetes insipidus is reportedly lower with transsphenoidal compared with transcranial resection, but the differences in anterior pituitary dysfunction is less marked.11,37,74,80,81,83,84,87,92 Recurrence after total resection of primary tumors occurs in 0 to 20% of patients, with the incidence of recurrence substantially less in the most experienced centers.80,81,83,89,92
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