Craniopharyngiomas

Introduction

Craniopharyngioma is a rare but important intracranial tumor that presents a unique challenge to the neurosurgeon. It has often been described as a histologically benign tumor that behaves in a malignant manner. This “malignancy” is due to a combination of its predilection for arising within and being closely apposed to exquisitely eloquent brain structures, its unpredictable biologic behavior, and its high local recurrence rates. Arising from the remnants of the Rathke pouch, the tumor itself—and attempts to treat it, either surgically or nonsurgically—can cause significant visual, endocrine, and neurocognitive morbidity. The challenges arising from this situation have long been recognized, and perhaps no other intracranial neoplasm has seen such dramatic changes in accepted treatment protocols over the decades. There have been changes in suggested management stratagems—from maximal resection based on achieving a radiologic cure, to more minimal procedures, often in combination with adjuvant therapies, focused on preserving function and minimizing the risk of recurrence. What has become increasingly clear is that there is no “one size fits all” approach for these complex entities, and each individual case must be assessed on its merits by a multidisciplinary team to achieve the best possible outcome. Despite the increasingly multidisciplinary management of craniopharyngioma, the neurosurgeon still plays the central role in decision making for affected patients.

Epidemiology

Craniopharyngioma is a rare tumor. Its incidence has been estimated at 1.3 cases per million people per year with the highest incidence in Japan and West Africa, particularly in Nigeria. Across all ages, craniopharyngiomas constitute only around 1% of all the new central nervous system tumors found per year, although this rises to 4% in the pediatric age group. There is a well-recognized bimodal age distribution, with the first peak occurring at school age (5–14) and a second occurring in middle to late adulthood (45–65). There is no gender predilection. The histologic diagnosis also varies with age, with the papillary form of craniopharyngioma being seen almost exclusively in the adult group, whereas adamantinomatous tumors can be found in both groups. No environmental or genetic risk factors have been identified, and craniopharyngioma is best thought of as a sporadic condition.

Embryology

Craniopharyngioma pathogenesis is believed to result from the unique embryology of the anterior pituitary gland. During development of the fetus, a pocket of epithelial ectoderm (the Rathke pouch), in the roof of the pharynx, extends superiorly to meet the neurectoderm of the developing brain. A temporary connection between the two ectodermal layers—the craniopharyngeal duct—thus forms. This then involutes, leaving glandular tissue to form the normal adenohypophysis or anterior pituitary gland. Adamantinomatous craniopharyngioma is thought to arise when, during this process, incomplete or erroneous involution of the Rathke pouch and craniopharyngeal duct occurs, leaving “nests” of epithelial rest cells that go on to undergo neoplastic change. Papillary tumors are postulated to form from metaplasia in the mature adult pituitary gland, with conversion of normal pituicytes into epithelial nests containing abnormal epithelial cells. These differing theories may explain the temporal distribution of the two craniopharyngioma types, as metaplasia is a slowly occurring process and it takes many years to generate the nests.

Anatomy

The anatomy of the sellar region is complex, and a neurosurgeon intending to operate on a craniopharyngioma must have a good three-dimensional grasp on the important osseous, arterial, venous, and neural relationships to the tumor. Within the suprasellar space, craniopharyngiomas are intimately related to the circle of Willis and its branches. The most important anatomic distinction is whether the tumor arises from above or below the sellar diaphragm, which dictates its relationship with surrounding anatomy as it grows. An appreciation of the premorbid arrangement of the optic chiasm—the so-called normal (above the midpoint of the sella), “prefixed” (above the tuberculum sellae) and “postfixed” (above the dorsum sellae) positions—is also essential when planning a surgical approach.

Tumors arising below the diaphragm (infradiaphragmatic craniopharyngioma) will push the sellar diaphragm and contents upward as they grow, eventually causing compression and upward displacement of the chiasm and third ventricle. Anatomically, their behavior is similar to that of an enlarging pituitary adenoma.

Craniopharyngiomas arising from above the sellar diaphragm (supradiaphragmatic) can be further divided depending on their point of origin—the pituitary stalk or the hypothalamic infundibulum. Those arising from the pituitary stalk will enlarge into the subarachnoid space below the chiasm and third ventricular floor, usually extending anteriorly into the region between the optic nerves (except in the rare case of a prefixed chiasm, where they may be entirely retrochiasmatic). These tumors are sometimes designated as suprasellar extraventricular craniopharyngiomas (SECs).

Craniopharyngiomas arising from the infundibulum tend to grow in both extra- and intraventricular fashion and are sometimes therefore called intraventricular and extraventricular craniopharyngiomas (IEVCs) ; this is the most commonly seen configuration. They are thought to grow in a retrochiasmatic manner and to erode and cross the floor of the third ventricle relatively early. This leads to a lower component extending in the suprasellar cistern and an upper part growing into the cavity of the third ventricle. IEVCs are almost always entirely retrochiasmatic, except in cases of a postfixed chiasm where some of the tumor may extend below the chiasm or even grow between the optic nerves.

A true “pure” intraventricular craniopharyngioma is a rare entity, with the majority of tumors thought to be exclusively enclosed within an intact third ventricle having some extension into the suprasellar space on close radiologic or surgical examination. Cases, however, have been described.

Ectopic craniopharyngiomas, occurring in locations other than the sellar region or even outside of the central nervous system, have been described but are exceedingly rare. “Seeding” of craniopharyngioma cells, causing distant recurrence adjacent to a surgical track or craniotomy used to resect a sellar lesion, is a rare but well-described occurrence. Primary “true” ectopic lesions are rarer still but have been described in central nervous system (CNS) locations such as the cerebellopontine angle, corpus callosum, and fourth ventricle and even extradurally in the ethmoid and sphenoid air sinuses.

Pathology

Craniopharyngioma, according to the 2007 World Health Organization (WHO) definition, is a “benign, partially cystic epithelial tumor of the sellar region, presumably derived from Rathke pouch epithelium” and is designated as a grade I tumor of the central nervous system.

Gross pathologic examination of craniopharyngiomas differentiates them into cystic (50%), mixed cystic-solid (35%), and solid (15%). They are typically described as lobulated masses with evidence of adherence to and disruption of surrounding structures such as the hypothalamus, infundibulum, blood vessels, or cranial nerves. On section, cysts are found to contain fluid that has a brownish color often described as “machine oil,” which on examination contains cholesterol crystals. In addition, calcification is frequently identified within the specimen. This classic macroscopic description is typical of the adamantinomatous subtype, with the papillary type more commonly solid without “machine oil” fluid or calcification.

The two subtypes are quite distinct on histologic examination. Adamantinomatous tumors are formed of “nests” of epithelium within gliotic neural stroma. Rows of tumor cell nuclei, or “palisading” nuclei, are often seen associated with stellate reticulum formed of loosely arranged epithelial cells. Mitotic figures are rare in keeping with the benign histologic grade. The histologic hallmark of craniopharyngioma is “wet keratin,” stacked arrays of plump, eosinophilic keratinized cells.

Papillary tumors, in contrast, are formed of bland stratified squamous epithelium with foci of fibrovascular tissue, without palisading or stellate reticulum. Keratinized cells are sometimes seen but not wet keratin.

Due to their characteristic histology, immunohistochemistry is not usually necessary to confirm diagnosis but is occasionally helpful. Both subtypes stain strongly for epithelial membrane antigen and cytokeratin. They are negative for “pituitary” markers such as prolactin and adrenocorticotropic hormone (ACTH).

Understanding of the molecular pathways involved in craniopharyngioma is incomplete, but many studies are ongoing. Mutations of the CTNNB1 gene, encoding β-catenin, have been described in adamantinomatous craniopharyngioma; accumulations of nuclear β-catenin, consistent with activation of the Wnt pathway, are identified in scattered cells within this craniopharyngioma type. By contrast, the BRAF C600E mutation is found in up to 100% of papillary craniopharyngiomas.

Radiology

The most useful imaging modality for assessing craniopharyngioma is magnetic resonance imaging (MRI), although computed tomography (CT) still has a role, particularly for assessing calcification (which can reliably differentiate craniopharyngioma from other suprasellar pathologies) and for detailed assessment of skull base anatomy for surgical planning. Plain skull radiography has been superseded by MRI and CT, whereas formal catheter angiography is only rarely indicated—to aid presurgical planning in large tumors that appear on MRI to have close relationships to the circle of Willis or if a giant suprasellar aneurysm is a differential diagnosis. Both MRI and CT demonstrate obstruction to cerebrospinal fluid (CSF) flow and hydrocephalus related to filling or distortion of the third ventricle, usually by a craniopharyngioma cyst.

MRI of craniopharyngioma usually demonstrates a heterogeneous mass. Solid components are usually T1 isointense and enhance with gadolinium contrast. Cystic components often demonstrate ring enhancement, whereas the cyst contents may vary in appearance depending on the protein or blood breakdown products contained therein. There may even be fluid-fluid levels within individual cysts or heterogeneity in signal characteristics between different cysts in the same tumor. MRI, ideally reviewed in three planes, identifies the topography of the tumor and can be used to divide craniopharyngiomas into infra- and supradiaphragmatic as described earlier. The former are usually associated with enlargement of the sella in a similar manner to pituitary adenoma. The latter group can be subdivided into SECs and IEVCs radiologically, using the anatomic criteria described previously.

An assessment of the position of the optic chiasm in relation to the tumor can usually be made accurately on MRI scan. If the chiasm itself cannot be directly visualized, the anterior communicating artery is a reliable marker of its position, this artery being usually apposed to the chiasm's upper posterior surface.

The differential diagnosis for sellar region lesions is wide and includes the Rathke cleft cyst, optic pathway glioma, hypothalamic hamartoma, metastasis, and others. CT can be useful in differentiating craniopharyngioma from these other differentials by demonstrating evidence of calcification; this is seen in 85% to 90% of childhood craniopharyngioma and around 40% to 50% of adult tumors. The relatively lower rate in adults can be explained by the presence of the papillary histologic subtype in that age group, as papillary craniopharyngiomas do not calcify. A note of caution here is that the only other lesion that may show similar rim or “eggshell” calcification is an aneurysm. Vascular imaging (CT, MRI, or catheter angiography) is indicated prior to surgical exploration if concern persists.

Decision making about the feasibility and extent of surgery is informed by close analysis of the preoperative MRI scan. The Paris group has published a system based on presurgical involvement of the hypothalamus to guide surgical decision making. The Paris classification is as follows: grade 0, no hypothalamic involvement; grade 1, the tumor abutting or displacing the hypothalamus; and grade 2, hypothalamic involvement (the hypothalamus is no longer identifiable). The implications of this presurgical radiologic grading system on operative results and outcome are discussed next.

Presentation

Craniopharyngioma can present with a wide variety of clinical symptoms and signs; all can be predicted by the relations of the suprasellar tumor to the critical surrounding structures. Symptoms can be visual (due to compression or injury to the optic apparatus), endocrine (hypothalamic-pituitary axis), neurocognitive (mammillary bodies, hypothalamus, and associated limbic tracts), and those of obstructive hydrocephalus (third ventricle). Patterns of initial presenting symptomatology differ between age groups, with endocrinopathies and hydrocephalus more common in children and visual impairment and neurocognitive changes more frequent in adults.

Visual impairment can take several forms, including field deficits and reduced acuity. The nature of the field deficit depends on the anatomic configuration of the tumor but can include bitemporal hemianopia, homonymous hemianopia, concentric field constriction, and central or paracentral scotoma, of which an asymmetric bitemporal hemianopia is the most common type. Field deficits are usually due to direct compression of the relevant part of the optic pathway by the enlarging craniopharyngioma but can represent ischemia caused by involvement of perforating arteries by the tumor. Reduced acuity is most commonly due to prolonged raised intracranial pressure such as that seen secondary to obstructive hydrocephalus, but it can be a late effect of prolonged compression. Children often do not report visual symptoms or impairment until they are profound, and it is sadly not uncommon for young patients to be functionally blind at first presentation.

Endocrinopathies are often insidious in their onset, and both children and adults often miss the symptoms. Children may show restricted growth or delayed onset of puberty. Adults may experience decreased libido and erectile dysfunction (men) or amenorrhea (in women). Diabetes insipidus and obesity may occur at any age. The presence of obesity suggests hypothalamic involvement.

Obstructive hydrocephalus causes the typical symptoms of raised intracranial pressure—namely, headache, nausea, drowsiness, and visual deterioration due to papilledema (and eventual optic atrophy). This presentation is much more common in the pediatric age group, presumably as adults will notice and report more subtle symptoms such as field deficits or neurocognitive impairment more readily than children.

In adults, neurocognitive symptoms can be the presenting feature, with memory impairment more common than personality change. These symptoms are thought to result from injury to the mammillary bodies or their connections with the hippocampus, fornix, and mammillary-thalamic tract caused by the expanding tumor.

Endocrine Assessment

It is essential that an appropriately trained and experienced endocrinologist is part of the multidisciplinary team caring for children and adults with craniopharyngioma. Endocrinopathies—resulting either from the effect of the tumor itself, at presentation or after multiple episodes of tumor progression, or as a result of treatment, surgical or otherwise—cause significant impairment of patients' quality of life and can be life threatening. Indeed, recognition of the importance of steroid replacement and endocrine expertise was one of the significant contributions to the reduction in perioperative mortality of craniopharyngioma surgery seen in the mid-20th century.

Although clinically under-recognized, 85% of patients have hypopituitarism at presentation, with growth hormone (GH) being the most common hormone affected, followed by luteinizing hormone/follicle-stimulating hormone (LH/FSH), with sequentially lesser rates of corticotropin (ACTH) and thyroid-stimulating hormone (TSH) deficiency. These deficiencies may be detected biochemically or be symptomatic, with the usual features evident clinically. Diabetes insipidus (DI), due to deficiency of antidiuretic hormone (ADH), has been reported in around a quarter of patients at diagnosis.

In addition to deficiencies of pituitary hormones, systemic symptoms may arise from hypothalamic dysfunction caused by tumor invasion or (more frequently) surgical disruption of this critical homeostatic structure. The typical hypothalamic symptom seen in craniopharyngioma (either pre- or postoperatively) is obesity resulting from injury to the satiety center located in the ventromedial nucleus, close to the floor of the third ventricle anterior to the mammillary bodies and therefore often involved in craniopharyngiomas. This hyperphagia and obesity often are accompanied by deterioration in behavior and school performance in children. Other hypothalamic symptoms are less frequent but can occur, including temperature dysregulation, disordered sleep, and deficient thirst.

All new cases of craniopharyngioma should have a full clinical and biochemical endocrine assessment at presentation and definitely prior to any surgical procedure. This should consist of a detailed clinical examination, including measurement of body mass index (BMI) and an assessment of intravascular volume status. The exact schedule of biochemical investigation will vary between institutions, dependent on the experience and preferences of the endocrine and laboratory services, but should include a full assessment, including dynamic testing if required, of the adrenal, thyroid, and gonadal axes, as well as GH, prolactin, and ADH function.

Management of both pre- and postoperative endocrinopathies involves exogenous replacement of deficient hormones. The most critical, and first to be replaced, are glucocorticoids. The administration of thyroxine, for example, in an untreated or undertreated steroid-deficient patient can precipitate acute adrenal crisis. When planning surgery, a plan for stress dosing (extra administration), intra- and postoperatively, should be made and requires close teamwork among the neurosurgical, anesthetic, and endocrine teams.

In the postoperative period, diabetes insipidus can be a feature, including the so-called triphasic response of initial polyuria, followed by oliguria and water retention, followed subsequently by a return of polyuria. Frequent monitoring of both serum and urine sodium, as well as osmolality, is mandatory, with the administration of ADH analogues when indicated. Although a transient diabetes insipidus–like condition is seen frequently in many postoperative craniopharyngioma patients, a subset will have long-term ADH replacement requirements.

Over time and multiple treatment modalities, pituitary deficiencies are ubiquitous in patients with craniopharyngioma, necessitating lifelong follow-up and, in children, careful transitional arrangements to appropriate adult expertise.

Neuro-Ophthalmologic Assessment

Detailed pre- and postoperative neuro-ophthalmologic examination is critical to objectively record visual impairment related to the tumor and the response (if any) to surgical treatment. It also establishes a baseline for subsequent follow-up. Examination should include funduscopy (ideally with photography of the fundus and optical coherence tomography) and perimetry (such as Goldmann or Humphrey testing) as well the usual documentation of visual acuity.

Fundal examination may reveal papilledema, almost exclusively seen in tumors presenting with hydrocephalus and its associated raised intracranial pressure, or optic atrophy, which may be a late result of either direct chiasmal compression or long-term, untreated raised intracranial pressure.

Field examination most typically reveals an asymmetrical bitemporal hemianopia, but more posterior lesions (or sellar lesions growing behind a prefixed chiasm) may cause a homonymous hemianopia. This homonymous hemianopia is incongruous and nonmacular sparing (so-called optic tract syndrome), differentiating it from the field cut seen with an occipitopolar lesion.

In children, strabismus may be a presenting feature. This strabismus is most frequently due to compensation for field loss and only rarely to involvement of the cranial nerves controlling ocular motility.