eMedicine Specialties > Neurology > Neuro-oncology

Craniopharyngioma

Author: George C Bobustuc, MD, Consulting Staff, Department of Neuro-Oncology, MD Anderson Cancer Center Orlando
Coauthor(s): Morris D Groves, MD, Assistant Professor, Department of Neuro-Oncology, MD Anderson Cancer Center, University of Texas; Gregory N Fuller, MD, PhD, Professor of Pathology, Chief, Section of Neuropathology, Department of Pathology, Division of Pathology and Laboratory Medicine, University of Texas MD Anderson Cancer Center; Franco DeMonte, MD, FRCSC, FACS, Professor of Neurosurgery, Mary Beth Pawelek Chair in Neurosurgery, The University of Texas, MD Anderson Cancer Center, Houston Texas
Contributor Information and Disclosures

Updated: Sep 4, 2009

Introduction

Background

Craniopharyngioma is a slow-growing, extra-axial, epithelial-squamous, calcified cystic tumor arising from remnants of the craniopharyngeal duct and/or Rathke cleft and occupying the (supra)sellar region. Two main hypotheses explain the origin of craniopharyngioma—embryogenetic and metaplastic; they complement each other and explain the craniopharyngioma spectrum.

Embryogenetic theory

This theory relates to development of the adenohypophysis and transformation of the remnant ectoblastic cells of the craniopharyngeal duct and the involuted Rathke pouch. Both the Rathke pouch and the infundibulum develop during the fourth week of gestation and together form the hypophysis. Both elongate and come in contact during the second month. The infundibulum is a downward invagination of diencephalon; the Rathke pouch is an upward invagination of the primitive oral cavity (ie, stomodeum).

The craniopharyngeal duct is the neck of the pouch, connecting to the stomodeum, which narrows, closes, and separates the pouch from the primitive oral cavity by the end of the second month. Thus, the pouch becomes a vesicle, which flattens and surrounds the anterior and lateral surfaces of the infundibulum. Walls of this vesicle form different structures of the hypophysis. Finally, this vesicle involutes into a mere cleft and may disappear completely. Rathke cleft, together with remnants of the craniopharyngeal duct, can be the site of origin of craniopharyngiomas.

Metaplastic theory

This theory relates to the residual squamous epithelium (derived from stomodeum and normally part of the adenohypophysis), which may undergo metaplasia.

Dual theory

This theory explains the craniopharyngioma spectrum, attributing the adamantinous type (most prevalent in childhood) to embryonic remnants and the adult type (ie, squamous papillary) to metaplastic foci derived from mature cells of the anterior hypophysis (prevalence of the adult type increases with each decade of life and is almost never found in children).

Other cystic lesions may originate from remnants of the stomodeum and pharyngohypophyseal duct as well, such as Rathke cleft cysts, epithelial cysts, epidermoid cysts, and dermoid cysts.

Pathophysiology

Craniopharyngiomas are dysontogenic tumors with benign histology and malignant behavior, as they have a tendency to invade surrounding structures and recur after what was thought to be total resection.

Craniopharyngioma usually presents as a single large cyst or multiple cysts filled with a turbid, proteinaceous material of brownish-yellow color that glitters and sparkles because of a high content of floating cholesterol crystals. Because of its appearance, it has been compared to machinery oil. It most frequently arises in the pituitary stalk and projects into the hypothalamus.

It extends horizontally along the path of least resistance in various directions—anteriorly into the prechiasmatic cistern and subfrontal spaces; posteriorly into the prepontine and interpeduncular cisterns, cerebellopontine angle, third ventricle, posterior fossa, and foramen magnum; and laterally toward the subtemporal spaces. It can even reach the sylvian fissure.

Rare locations include extradural and extracranial—nasopharyngeal or pure posterior fossa craniopharyngiomas, or craniopharyngiomas extending down the cervical spine. Purely intraventricular craniopharyngioma is usually of the squamous-papillary (metaplastic) type; it occurs very rarely.

Clinical behavior and choice of surgical approach are dictated by the primary location of the tumor and its extension pattern. Both prechiasmatic craniopharyngioma (extending into subfrontal spaces) and retrochiasmatic craniopharyngioma (expanding into the posterior fossa) may reach large sizes before being diagnosed.

Vascular supply is dependent on different sources, usually all from the anterior circulation. The anterior portion of the tumor is supplied by small perforators coming off A1 (ie, anterior cerebral artery); lateral portions receive perforators from the proximal portion of the posterior communicating artery; and the intrasellar part is supplied by branches of the intracavernous meningohypophyseal arteries. Craniopharyngioma rarely is supplied with blood coming from the posterior circulation, unless the anterior blood supply for the anterior hypothalamus and floor of the third ventricle is lacking.

Tumor adhesion to surrounding vascular structures represents the most common cause of incomplete tumor removal. Fusiform dilatations of large surrounding vessels have been reported after attempts at radical dissection of the tumor capsule; they injure vasa vasorum, thereby weakening the adventitia. Tumor adhesion is the result of local inflammation.

Several inflammatory cytokines have been shown to be elevated in the craniopharyngioma cyst fluid when compared with CSF. IL-1alpha and TNF-alpha were significantly elevated but lower than 10-fold. IL-6 was greater than 50,000 times more concentrated in the cystic fluid than CSF.¹ This supports the hypothesis that biomodulation of the cytokine profile could lead to long periods of stability and even tumor regression. IFN-alpha exerts diverse influences mainly on cytokine antagonists and soluble adhesion molecules and has been shown to play a role in the treatment of craniopharyngioma in some limited trials, both after systemic use and local, direct intracystic use.²

Recurrences usually occur at the primary site. Ectopic and metastatic recurrences are extremely rare and have been reported after surgical removal. The two possible mechanisms of seeding are dissemination of tumor cells along the surgical paths during the procedure and migration of tumor cells through the subarachnoid space or Virchow-Robin spaces (which would explain ectopic recurrences distant from the surgical bed and within brain parenchyma).

In one metastatic case, after removal of a suprasellar (adamantinomatous) craniopharyngioma, 2 peripheral lesions were identified 7 years later, adjacent to the dura and contralateral to the initial craniotomy site. They proved to be adamantinomatous tissue raising the possibility of meningeal seeding. In another reported case, an adamantinomatous craniopharyngioma recurred at different intervals, at different sites, along the operative track of the initial surgical procedure and distant, within the brain parenchyma, thus, suggesting involvement of both seeding mechanisms. In a large retrospective review, histopathologic type of craniopharyngioma and/or brain invasion did not correlate with risk of recurrence.³

MIB-1 labeling index is a measure of the proliferative activity; it is determined by using an immunohistochemical method with monoclonal antibody MIB-1 and may be useful for planning of adjuvant therapy. A recent small study found that an MIB-1 labeling index greater than 7% predicted regrowth/recurrence.

Genomic and molecular biology of craniopharyngiomas

Comparative genomic hybridization (CGH) studies have been reported with conflicting results. CGH sensitivity is limited to deletions of the order of several megabases, and, thus, smaller deletions or balanced alterations could be missed. Some suggest that chromosomal imbalances⁴ do not play a significant role in tumorigenesis of both papillary and adamantinomatous craniopharyngiomas. Others report a small subset of adamantinomatous craniopharyngiomas showing a significant number of genetic alterations and abnormal DNA copy number, thus suggesting a monoclonal origin driven by the activation of oncogenes located at specific chromosomal loci.⁵

Adamantinomatous craniopharyngiomas have been consistently reported to show alterations in the beta-catenin gene expression.^6,7,8 Expression of beta-catenin correlates with some of the hallmarks ("wet" keratin, calcifications and palisading cells) of adamantinomatous craniopharyngiomas. This abnormality has not been reported in papillary craniopharyngiomas.

Beta-catenin is a transcriptional activator of the Wnt signaling pathway and a component of the adherence junction. Wnt signaling pathway has been proven to play a crucial role in embryogenesis and cancer. Wnt signaling is involved in determination of cell fate, proliferation, adhesion, migration, polarity, and behavior during development and plays an intricate role in the temporal and spatial regulation of organogenesis. Wnt complex comprises 3 different pathways: canonical, noncanonical, and Wnt/Ca⁺². Canonical pathway regulates cell fate determination and primary axis formation through gene transcription. Noncanonical pathway regulates cell movements through modification of the actin cytoskeleton. Wnt/Ca⁺² pathway is involved in regulation of both cell movement and fate determination.

Immunohistochemistry for beta-catenin in adamantinomatous craniopharyngiomas showed an abnormal cytoplasmic and nuclear accumulation. The normal membranous staining was present in both adamantinomatous and papillary craniopharyngiomas.

Sequencing analysis revealed beta-catenin gene mutations in adamantinomas, while none were found in papillary craniopharyngiomas. All mutations were missense mutations involving the serine/threonine residues at GSK-3beta (glycogen synthase kinase-3beta) phosphorylation sites or an amino acid flanking the first serine residue. These mutations are considered to lead to beta-catenin accumulation as a result of impaired proteosome degradation due to ineffective phosphorylation by a mutated GSK-3beta.

Furthermore, Wnt/beta-catenin signaling pathway has been shown to prevent differentiation (of mouse embryonic stem cells) through convergence on the LIF/Jak-STAT (leukemia inhibitory factor/Janus kinase-signal transducer and activator of transcription) pathway at the level of STAT3.⁹ Interferons are known modulators of Jak/STAT pathways, thus revealing the possible molecular basis for interferons as therapeutic option in adamantinomatous craniopharyngiomas.

Some craniopharyngiomas express growth hormone (IGF-1R) and sex hormone receptors (ER and PR). Despite reported sporadic expression of IGF-1R in 2 large retrospective reviews (including children and adults) where treatment duration mean was 6 years and mean follow-up was approximately 10 years, no evidence was found to suggest increased recurrence rates in patients who received growth hormone supplementation.^10,11 ER and PR expression in 1 correlative study was linked to higher differentiation and a decreased incidence of tumor recurrence and was proposed as a tool for recurrence risk stratification.

Other markers were proposed for noninvasive clinical monitoring. Urinary matrix metalloproteinases (MMPs, nonspecific tumor invasion markers) in one case were reported to be a useful predictor of disease activity and risk of recurrence.¹²

Expression of human minichromosome maintenance protein 6 (MCM6) and DNA topoisomerase 2 alpha (DNA Topo 2 alpha) were proposed as histologic markers associated with a higher risk of recurrence in adamantinomatous craniopharyngiomas.

Frequency

United States

Data from the Central Brain Tumor Registry of the United States (CBTRUS), collected between 1990 and 1993, revealed an average of 338 cases diagnosed annually with 96 occurring in children aged 0-14 years.¹³

• Overall incidence was 0.13 per 100,000 per year.
• No variance by gender or race was found.
• Craniopharyngioma comprised 4.2% of all childhood tumors (ages 0-14 years).
• Distribution by age was bimodal, with peak incidence in children aged 5-14 years and older adults aged 65-74 years.

International

Incidence is 0.5-2 per 100,000 per year.

• Overall, craniopharyngioma accounts for 1-3% of intracranial tumors and 13% of suprasellar tumors.
• In children, craniopharyngioma represents 5-10% of all tumors and 56% of sellar and suprasellar tumors.
• No definite genetic relationship has been found and very few familial cases have been reported.

Mortality/Morbidity

• In the United States, data collected during the periods 1985-1988 and 1990-1992, coinciding with the introduction of CT scan, for the National Cancer Data Base (NCDB), indicate that survival rates were 86% at 2 years and 80% at 5 years after diagnosis.
• Survival rate varied by age group, with excellent rates for patients younger than 20 years (99% at 5 years).
• Survival rate was poor for those older than 65 years (38% at 5 years).

Race

Higher frequencies of all intracranial tumors have been reported from Africa, the Far East, and Japan; they are 18%, 16%, and 10.5%, respectively.

Sex

Slight male predominance exists in all age groups (55%).

Age

• Age of diagnosis varies widely; cases have been reported both in fetuses and in the elderly (age as high as 70 years).
• Age distribution is bimodal–the first peak is in children aged 5-10 years and a second one is in adults aged 50-60 years.

Clinical

History

Craniopharyngioma usually is a slow-growing tumor. Symptoms frequently develop insidiously and mostly become obvious only after the tumor attains a diameter of about 3 cm. Time interval between onset of symptoms and diagnosis ranges from 1-2 years.

• The most common presenting symptoms are headache (55-86%), endocrine dysfunction (66-90%), and visual disturbances (37-68%).
  • Headache is slowly progressive, dull, continuous, and positional; it becomes severe in most patients when endocrine symptoms become obvious.
  • On presentation, 40% of patients have symptoms of hypothyroidism (eg, weight gain, fatigue, cold intolerance, constipation). Almost 25% have associated signs and symptoms of adrenal failure (eg, orthostatic hypotension, hypoglycemia, hyperkalemia, cardiac arrhythmias, lethargy, confusion, anorexia, nausea and vomiting), and 20% have diabetes insipidus (eg, excessive fluid intake and urination).
  • Eighty percent of adults complain of decreased sexual drive and almost 90% of men complain of impotence, while most women complain of amenorrhea.
  • Most young patients present with growth failure and delayed puberty.
  • Optic pathway dysfunction on presentation is noted in 40-70% of patients. Children rarely become aware of visual problems (only 20-30%) and often present after almost complete visual damage has taken place.
  • Other manifestations relate to the various connections of the hypothalamic-pituitary complex and surrounding structures. Thalamus and frontal lobes present with corresponding endocrine, autonomic, and behavioral problems (eg, hyperphagia and obesity, psychomotor retardation, emotional immaturity, apathy, short-term memory deficits, incontinence).
  • Short stature is present in 23-45% and obesity in 11-18%.
• Three major clinical syndromes have been described and relate to the anatomic location of the craniopharyngioma.
  • Prechiasmal localization typically results in associated findings of optic atrophy (eg, progressive decline of visual acuity and constriction of visual fields).
  • Retrochiasmal location commonly is associated with hydrocephalus with signs of increased intracranial pressure (eg, papilledema, horizontal double vision).
  • Intrasellar craniopharyngioma usually manifests with headache and endocrinopathy.

Physical

Both neurologic and general examinations are indicated.

• Neurologic examination
  • Signs suggestive of increased intracranial pressure, both horizontal double vision (unilateral/bilateral) and papilledema (unilateral/bilateral), should be sought in any patient suspected of having an intracranial mass.
  • Visual field examination may reveal various patterns of visual loss (most frequently bitemporal hemianopsia) suggestive of involvement (ie, compression) of the optic chiasma and/or tracts; visual fields should be tested further with formal testing.
• General examination - May reveal signs relating to different endocrinopathies
  • Hypothyroidism: Symptoms of hypothyroidism include puffiness and nonpitting edema, slow return phase of deep tendon reflexes, long-standing effects on organ systems, hypoventilation and decrease in cardiac output, pericardial and pleural effusions, constipation, anemia (ie, normochromic normocytic), decreased mental function, and psychiatric changes.
  • Adrenal insufficiency
    • Cortisol deficiency: This results in hypotension, which is often orthostatic. Gastrointestinal symptoms include anorexia, nausea, and vomiting; other signs and symptoms include weight loss, hypoglycemia, lethargy, confusion, psychosis, and intolerance to stress.
    • Aldosterone deficiency: Signs and symptoms include hypovolemia, decreased cardiac output, decreased renal blood flow with azotemia, fatigue, weight loss, and cardiac arrhythmias due to hyperkalemia.

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