eMedicine Specialties > Neurology > Neuro-oncology

Craniopharyngioma

George C Bobustuc, MD, Consulting Staff, Department of Neuro-Oncology, MD Anderson Cancer Center Orlando
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

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.

Differential Diagnoses

Other Problems to Be Considered

Brainstem syndromes
Increased intracranial pressure

Other tumors
Epidermoid and dermoid tumor
Germ cell tumor
Hypothalamic-optic pathway glioma
Meningioma
Metastasis
Hypothalamic hamartoma
Pituitary tumor

Infectious or inflammatory processes
Histiocytosis X
Infundibulitis
Lymphocytic hypophysitis
Sarcoidosis
Syphilis
Tuberculosis

Vascular malformations
Carotid-cavernous fistula
Cavernous sinus hemangioma
Giant suprasellar carotid aneurysm

Other congenital defects
Arachnoid cyst
Rathke cleft cyst

Workup

Laboratory Studies

• The diagnostic evaluation for craniopharyngioma includes precontrast and postcontrast CT scans and MRI, magnetic resonance angiography (MRA), complete endocrinologic and neuro-ophthalmologic evaluation with formal visual field documentation, as well as neuropsychological assessment.
• Endocrinologic studies
  • These should include baseline serum electrolytes, serum and urine osmolality, thyroid studies, morning and evening cortisol levels, growth hormone levels, and luteinizing and follicle-stimulating hormone levels (in adolescent and adult patients).
  • Extending the workup for various hypothalamic-releasing factors allows for differentiation between endocrine disorders of pituitary origin and those of hypothalamic origin. It also helps in correlating various neurohormonal deficits with neuropsychological deficits.
  • In emergency cases, hormonal testing should be limited to diagnosing diabetes insipidus and hypoadrenalism, as both require initiation of treatment prior to surgery.

Imaging Studies

• Imaging studies strongly suggest the diagnosis. The radiologic hallmark of a craniopharyngioma is the appearance of a (supra)sellar calcified cyst. About 80-87% of craniopharyngiomas are calcified and 70-75% are cystic. Calcifications are more common in children (90%) than in adults (50%).
• CT scan is the most sensitive method to demonstrate calcifications as high-density areas and has replaced the plain radiograph. It is useful in defining both calcified and cystic parts. Cyst content usually has the same density as CSF; contrast administration better defines the enhancing cyst capsule.
• MRI, with its multiplanar capability, is essential for defining the local anatomy and is the most important imaging modality used to plan the surgical approach.
• MRA is used for visualizing the major cerebral vessels and their relation to the tumor; it has largely replaced the 4-vessel angiogram.

Other Tests

• Neuro-ophthalmologic evaluation with formal visual field documentation
• Neuropsychological assessment

Histologic Findings

The histologic spectrum of craniopharyngioma includes 3 main types—adamantinomas, papillary, and mixed.

• Adamantinomas consist of reticular epithelial masses, resembling the enamel pulp of developing teeth. This is seen predominantly in children. A distinctive feature is a palisading basal layer of small cells, which encloses a loose stellate reticular zone, as well as areas of compactly arranged squamous cells. They contain nodules of keratin ("wet" keratin), which are the hallmarks of this tumor subtype (see Media files 1-5).
  
  

  

  The adamantinomatous craniopharyngioma is a histologically complex epithelial lesion with several very distinctive morphologic features. Each of these features is shown under higher power in Images 2-5 (hematoxylin-eosin, x40).

  
  
  
  

  

  Adamantinomatous craniopharyngiomas. Peripheral palisading of the epithelium is a pronounced feature (hematoxylin-eosin, x100).

  
  
  
  

  

  Adamantinomatous craniopharyngiomas. Frequently, the inner epithelium beneath the superficial palisade undergoes hydropic vacuolization and is referred to as the stellate reticulum (hematoxylin-eosin, x100).

  
  
  
  

  

  Adamantinomatous craniopharyngiomas. Another distinctive feature of the adamantinomatous variant is scattered nodules of keratin. These nodules are referred to as "wet" keratin because of the plump appearance of the keratinocytes; this is in contrast to the flat, flaky keratin seen in epidermoid and dermoid cysts (hematoxylin-eosin, x100).

  
  
  
  

  

  Adamantinomatous craniopharyngiomas. Nodules of "wet" keratin frequently calcify; in aggregate, this calcification often can be detected on CT scans, and is a recognized radiologic feature of craniopharyngiomas (hematoxylin-eosin, x100).

  
  
• Squamous papillary type is composed of islands of squamous metaplasia, embedded in a connective tissue stroma, with infrequent cystic degeneration and calcification. This subtype rarely is seen in children and does not form keratin nodules (see Media files 6-7).
  
  

  

  Papillary craniopharyngioma. In contrast to the adamantinomatous variant, papillary craniopharyngiomas do not show complex heterogeneous architecture (compare with Image 1) but rather are composed of simple squamous epithelium and fibrovascular islands of connective tissue (hematoxylin-eosin, x40).

  
  
  
  

  

  Papillary craniopharyngiomas. Under high power, only simple squamous epithelium is seen in a papillary craniopharyngioma. The distinctive peripheral nuclear palisading, internal stellate reticulum, and nodules of "wet" keratin, which typify the adamantinomatous variant, are not seen in the papillary variant (hematoxylin-eosin, x100).

  
  
• The brain parenchyma that surrounds both variants of craniopharyngioma is typically gliotic and often shows profuse numbers of eosinophilic Rosenthal fibers, which are composed of densely compacted bundles of glial filaments and typically are seen in astrocytic cell processes of neuropils that have been subjected to chronic compression from slowly expanding mass lesions (see Media file 8).
  
  

  

  Rosenthal fibers in neuropils surrounding a craniopharyngioma. The brain parenchyma that surrounds both variants of craniopharyngioma is typically gliotic and often shows profuse numbers of eosinophilic Rosenthal fibers. The latter structures are composed of densely compacted bundles of glial filaments and typically are seen in astrocytic cell processes of neuropils that have been subjected to chronic compression from slowly expanding mass lesions. Rosenthal fibers are a characteristic feature of juvenile pilocytic astrocytomas (JPAs), which also may arise in the suprasellar/third ventricular region. Hence, a biopsy that samples only the surrounding neuropil of a craniopharyngioma may yield an erroneous diagnosis of JPA if the pathologist is unaware of the close association of craniopharyngioma with Rosenthal fiber formation (hematoxylin-eosin, x100).

  
  

Treatment

Medical Care

Essentially, 2 main management options are available for craniopharyngioma—(1) attempt at gross total resection or (2) planned limited surgery followed by radiotherapy.

Although no consensus exists on the various therapeutic modalities for craniopharyngiomas, most authors advocate that successful management is determined by the ability to maintain independent social functioning, symptomatic recurrence, and survival.

• Neuropsychological deficits represent the major limiting factor of independent social functioning because (1) patients often can overcome minor neurological deficits and (2) hormone-repleting therapies are widely available. Degree of psychosocial impairment correlates directly with the degree of hypothalamic injury sustained at the time of surgery.
• Systemic chemotherapy has been tried but to no avail.
• New systemic biologic therapies are currently under investigation with interesting results (eg, interferon alpha-2a for progressive or recurrent craniopharyngiomas).

Surgical Care

Gross total surgical removal is the treatment of choice; however, it can be associated with morbidity and mortality rates as high as 20% (excluding endocrinopathies) and 12%, respectively. Recurrence rates can be as high as 20%; a serious potential for psychosocial deficits exists in patients with hypothalamic injury.

• The surgical approaches for resection of craniopharyngioma include the standard pterional approach, the orbitocranial approaches, as well as the subfrontal, transsphenoidal, and transcallosal approaches. At times, a combination of approaches is necessary.
  • Perioperative morbidity includes (1) seizures, (2) visual deficits including blindness, (3) hypothalamic injury, (4) stroke, and (5) CSF leakage.
  • Endocrinopathy is common. Permanent diabetes insipidus occurs in 68-75% of adults and 80-93% of children. Replacement of 2 or more of the anterior pituitary hormones is necessary in 80-90% patients. Obesity occurs in 50% of patients.
  • Recurrence/progression following failed gross total or subtotal resection is common and occurs in 75% of patients. Recurrence usually is identified 2-5 years following resection.
• Some authors propose a plan of limited surgery, with postoperative radiotherapy as the management paradigm of choice for craniopharyngioma. Goals of this approach are (1) pathologic confirmation of the tumor and (2) surgical decompression of the optic chiasma. Surgery is followed by external beam radiation, at a dose of 5400-5500 cGy delivered at 180 cGy/fraction.
  • The incidence of tumor progression after planned limited surgery and radiotherapy ranges from 12-25% and is similar to that seen with failed gross total resection and radiotherapy (4-25%).
  • Radiotherapy delivered at recurrence (salvage radiotherapy) is effective, with posttreatment progression rates of 29%. Recurrence following radiotherapy has been associated with a 50-80% mortality rate.
• Thus, the optimal approach should consider total removal safe (ie, no hypothalamic injury) or otherwise combine a subtotal resection (ie, removal of as much tumor as possible with no hypothalamic injury) with postoperative radiotherapy.
• For selected patients with suprasellar craniopharyngiomas, an endonasal extended endoscopic approach could provide a viable alternative to transcranial approaches.^14,15
• Other approaches that can be useful in the management of giant craniopharyngioma, especially at the time of recurrence, include (1) intermittent aspiration by stereotactic puncture or Ommaya reservoir placement, (2) intracystic injection of bleomycin,¹⁶ or (3) internal irradiation with radioisotopes. The latter 2 treatment modalities have been reported to control the tumor cysts in 90-100% of cases. In general, the 10-year survival rate for craniopharyngiomas is 90% and the 20-year survival rate for pediatric craniopharyngiomas is approximately 60%.

Medication

Agents/modalities used in the treatment of craniopharyngioma include (1) bleomycin for local intracystic chemotherapy^17,18,19 and (2) radiation therapy applied as external fractionated radiation, stereotactic radiation, or brachytherapy (intracavitary irradiation).^{20,21,22,23,24}

Chemotherapeutic agents

In combination with other drugs, these are used frequently and systemically against epithelial tumors. In the early 1970s, bleomycin was found to have encouraging results in controlling craniopharyngioma tissue in cultures. Intracavitary bleomycin reduces cyst size and toughens and thickens the cyst wall, thereby facilitating surgical excision of a cyst membrane that otherwise might fragment at the time of open craniotomy. However, reports of intracystic bleomycin use are limited.

Bleomycin (Blenoxane)

Group of glycopeptides extracted from Streptomyces species. Each molecule has a planar end and an amine end; different glycopeptides of the group differ in their terminal amine moieties. Planar end intercalates with DNA, while amine end facilitates oxidation of bound ferrous ions to ferric ions, thereby generating free radicals, which subsequently cleave DNA, acting specifically at purine-G-C-pyrimidine sequences.
Not absorbed when given orally; peak levels reached in about 30-60 min when given IM and are only one third of levels obtained after IV administration; approximately 50% of drug absorbed systemically after intrapleural or intraperitoneal administration; systemic absorption after intracavitary administration for craniopharyngioma not negligible.
Volume of distribution is 20-30 L both in intracellular and extracellular fluid.
Less than 10% is bound to plasma proteins.
Bleomycin has plasma half-life of less than 1 h and terminal half-life of 2-4 h, but it could be as long as 22 h in patients with renal dysfunction or those previously treated with cisplatin.
About 50% eliminated in urine within 24 h. Most tissues (known exceptions—skin and lungs) contain an enzyme, bleomycin hydrolase (most active tissues are liver and kidney), which readily inactivates drug; therefore, toxicity is tissue specific, occurring in tissues lacking this enzyme. Bleomycin mostly used systemically in combination with other drugs (mostly with cisplatin and vincristine) for treatment of testicular carcinoma, Hodgkin lymphoma, and non-Hodgkin lymphoma; squamous cell carcinoma of skin, head and neck, and cervix; and malignant pleural effusions.
Principal mechanisms of resistance include high levels of bleomycin hydrolase, cell mutations altering DNA sequences to prevent intercalation, poor cell accumulation of drug, and rapid plasma removal. None of these factors plays important role when bleomycin administered locally in residual cyst.
Toxicity is age dependent and cumulative dose related; systemic administration mostly causes pulmonary toxicity. This consists of pneumonitis, which can progress to fatal pulmonary fibrosis.
Maximum recommended total cumulative dose for systemic use is 400 U. Unit measurement based on toxicity to bacteria; 1 U equals approximately 1.7 mg.
Administered systemically, does not produce significant bone marrow toxicity. Toxicity with local administration due to both systemic contamination (when anaphylactoid reactions, transient fever, nausea, and vomiting could occur) and leakage into surrounding neural tissue. Fatal outcome has been reported with leakage, due to subsequent diffuse diencephalon and brainstem edema. Others report transient local toxicity with leakage into the surrounding brain reversed by high-dose steroid use.
Contrast CT cystography is required prior to intracavitary administration to ensure cyst wall integrity; when inconclusive, MR cystography with gadopentetate dimeglumine has been advocated.

Dosing

Adult

For local administration in residual cyst, dose depends on cyst volume, and repeated administrations are usually required
Varying dosages in repeated administrations intracavitary to a total cumulative dose of 40-80 mg over 7-21 days or longer intervals of 5- 10 weeks were reported, done with a frequency of 3 times/week with 3-5 mg intracystic/dose initially for first 5 weeks and followed by weekly administrations for another 5 weeks.
Lower dose per treatment session may help avert a fatal outcome in the rare case when leakage occurs into the surrounding brain.

Pediatric

Not established

Interactions

Phenothiazine may enhance cytotoxicity; cisplatin decreases elimination, thereby enhancing toxicity; radiation and hyperoxia may increase pulmonary toxicity; hydrogen peroxide and ascorbic acid inactivate bleomycin

Contraindications

Documented hypersensitivity; significant renal function impairment; compromised pulmonary function

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Intracavitary administration requires prior contrast CT cystography to ensure cyst wall integrity; when inconclusive, MR cystography with gadopentetate dimeglumine has been advocated

Radiation

Radiation creates free oxygen ions that damage cellular DNA. Cellular ability to repair DNA is lower for tumor cells than normal cells and subsequently, with each mitosis, a higher cumulative effect in tumor cells results in apoptosis.

External fractionated radiation

Offers dual advantage by (1) allotting normal cells more time for repair and (2) amplifying higher cumulative effect of DNA damage in more rapidly dividing tumor cells.
Radiation, following partial resection, offers excellent long-term results (80% at 20 years). Following partial resection, results of primary irradiation are superior to those with radiation delayed until time of recurrence. Recurrence is less frequent after imaging confirmed total resection (10-30% recurrence rate), in which case radiation should be delayed.

Dosing

Adult

Target volume for craniopharyngioma is narrowly confined to tumor volume (preoperative volume plus 1.5-cm margin) and should include solid component and cyst(s); should be limited to postoperative residual tumor in case of partial resection of large (multi) cystic craniopharyngioma, with special attention to cover cyst wall; high-energy photons are used with 2-3 stationary fields or classic coronal arc configuration
Radiotherapy target dose should be 54-56 Gy over 30 sessions (over 6 wk; Monday-Friday weekly schedule), at 1.8-2 Gy/session (ie, per day)
Dose <54 Gy has been associated with high recurrence rate (about 50%) while doses of 54 Gy or more associated with recurrence rate of only 15%
Dose >60 Gy associated with marked increase in radiologic-induced endocrine, neurologic, and vascular complications

Pediatric

Not established

Interactions

None reported

Contraindications

Imaging confirmed total resection (10-30% recurrence rate)

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Fetal exposure is <0.1 Gy (0.04-0.09% of tumor dose) at usual doses (50-68 Gy) used for brain irradiation; this confers increased (but acceptable) risk of leukemia in children, with no deleterious effects to fetus after fourth week of gestation
Radiotherapy should be avoided completely in children <3-4 y
Complications of radiotherapy include intellectual decline, radiation-induced necrosis, optic neuropathy, pituitary-hypothalamic damage, secondary malignant brain tumors; vascular abnormalities that occasionally lead to vasospasm; self-limiting, mostly asymptomatic, hemorrhages; less commonly, proximal irradiation of carotid arteries leads to development of Moyamoya disease

Brachytherapy/radioisotopes

Recommended for solitary cystic craniopharyngiomas and consists of stereotactic aspiration of cystic content, followed by instillation of beta-emitting isotope (eg, phosphorus 32, rhenium 186, gold 198, yttrium 90).
Brachytherapy is attractive because about 60% of craniopharyngiomas occur as single large cysts; early refilling is the rule, requiring intermittent aspiration either by stereotactic puncture or Ommaya reservoir.
Stereotactic radiation has been used for further treatment of residual solid tumor after brachytherapy.

Dosing

Adult

Target radiation dose 200-250 Gy, aimed at inner surface of cyst wall, which is far higher than dose that can be administered safely with external beam radiation
Maximum range of beta particles from phosphorous 32 in soft tissue is approximately 8 mm; more than half the dose absorbed by first 1.5 mm of tissue, which allows ablation of secretory cells within cyst wall without significant irradiation of surrounding brain tissue
Brachytherapy offers both (1) advantage of high reduction in dose to normal surrounding tissues (eg, optic chiasma, hypothalamus) and (2) an option for patients who received prior external beam radiation; brachytherapy usually results in stabilization or reduction of cyst in >90% of cases

Pediatric

Not established

Interactions

Not established

Contraindications

Imaging confirmed total resection (10-30% recurrence rate)

Precautions

Pregnancy

C - Fetal risk revealed in studies in animals but not established or not studied in humans; may use if benefits outweigh risk to fetus

Precautions

Acute inflammatory reactions reported following brachytherapy (some authors have advocated routine use of steroids)

Stereotactic radiation

Has been used primarily as first-line for treatment of growing or symptomatic, solid, small (sized) size craniopharyngioma (<25-30 mm in diameter). Stabilization or reduction of cystic cavity after radiosurgery achieved in more than 60% of patients.

Dosing

Adult

High-dose volume should be limited to well-circumscribed tumor; safety margin of at least 3-5 mm from optic nerve recommended

Pediatric

Not established

Interactions

None reported

Contraindications

Imaging confirmed total resection (10-30% recurrence rate)

Precautions

Pregnancy

B - Fetal risk not confirmed in studies in humans but has been shown in some studies in animals

Precautions

Major complications include visual impairment; >30% of patients experience severe visual deterioration; <10% of patients show rapid visual loss
Fetal exposure is <0.1 Gy (0.04-0.09% of tumor dose) at usual doses (50-68 Gy) used for brain irradiation, which confers increased but acceptable risk of leukemia in children; no deleterious effects to fetus after fourth week of gestation reported

Follow-up

Further Outpatient Care

• Postsurgical follow-up should be planned in 1-2 weeks for all patients.
• Patients with subtotal resections and candidates for external beam radiation therapy should start radiation within 3 weeks of surgery. Patients with either complete resections or completed radiation should be seen every 3 months for the first postsurgical year, every 6 months for the second and third years, and yearly thereafter.
• Each follow-up visit should include (1) a brain MRI that should be used for comparison with previous films and (2) correlation of the MRI with the clinical examination and neurocognitive testing results. As a rule, consider neurocognitive testing for (1) presurgery and postsurgery patients or (2) patients who underwent subtotal resection followed by radiation. All patients should have neurocognitive testing whenever declining performance (eg, school, work) is a concern or clinical examination reveals worsening neurocognitive deficits (eg, problem solving, language, memory, apraxia).
• In some patients, deficits encountered are related to radiation injury. These could be sorted out easily by the specific MRI findings and neurocognitive testing results. Subsequently, specific treatments can be employed. Close monitoring of endocrine symptoms, accompanied by confirmatory laboratory tests, is recommended for all patients. Most patients require several adjustments of their supplemental hormonal therapy during their postsurgical/postradiation phase and even years later. Prior radiotherapy treatment was reported to not compromise the beneficial effects of GH replacement therapy.
• Aggressive preventive management of long-term multisystem morbidities is key for long-term survival. A multiteam comprehensive approach is strongly recommended.
  • Panhypopituitarism was reported to be present in almost 90% of patients followed up for more than 10 years. Endocrinology long-term follow-up and monitoring is strongly recommended.
  • At 10 years, other highly prevalent morbidities were neurological (49%), psychosocial (47%), and cardiovascular (22%). Female sex is reported as an independent predictor of increased cardiovascular, neurological, and psychosocial morbidity. Long-term follow-up should include appropriate endocrine replacement²⁵ (to include estrogen in premenopausal women) and aggressive control of cardiovascular risk factors (blood pressure, weight, lipids, and glucose).
• Immunohistochemical studies and case reports caution on the possibly higher incidence of recurrence in patients receiving growth hormone and/or sex hormone replacement, as some craniopharyngiomas express IGF-1R, ER, and PRs. 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 (GH) supplementation.^10,11 Close imaging follow-up (every 4-6 wk) and clinical monitoring would be indicated if sex hormone and/or growth hormone replacement is pursued.

Miscellaneous

Medicolegal Pitfalls

• No consensus of opinion exists concerning the appropriate management of craniopharyngiomas. No guidelines have yet been established by the American Academy of Neurology Neuro-oncology section.
• Most of the accepted management strategies are from retrospective reviews; no prospective randomized clinical trials have been conducted to compare the various therapeutic modalities.
• To date, no standard-of-care issues have reached the appeals-court level to provide case law on which to base future treatment decisions.
• The usual precautions regarding treatment of elevated intracranial pressure and surveillance for potentially life-threatening endocrinopathies should be exercised when treating patients with craniopharyngioma.

Multimedia

Media file 1: The adamantinomatous craniopharyngioma is a histologically complex epithelial lesion with several very distinctive morphologic features. Each of these features is shown under higher power in Images 2-5 (hematoxylin-eosin, x40).

Media file 2: Adamantinomatous craniopharyngiomas. Peripheral palisading of the epithelium is a pronounced feature (hematoxylin-eosin, x100).

Media file 3: Adamantinomatous craniopharyngiomas. Frequently, the inner epithelium beneath the superficial palisade undergoes hydropic vacuolization and is referred to as the stellate reticulum (hematoxylin-eosin, x100).

Media file 4: Adamantinomatous craniopharyngiomas. Another distinctive feature of the adamantinomatous variant is scattered nodules of keratin. These nodules are referred to as "wet" keratin because of the plump appearance of the keratinocytes; this is in contrast to the flat, flaky keratin seen in epidermoid and dermoid cysts (hematoxylin-eosin, x100).

Media file 5: Adamantinomatous craniopharyngiomas. Nodules of "wet" keratin frequently calcify; in aggregate, this calcification often can be detected on CT scans, and is a recognized radiologic feature of craniopharyngiomas (hematoxylin-eosin, x100).

Media file 6: Papillary craniopharyngioma. In contrast to the adamantinomatous variant, papillary craniopharyngiomas do not show complex heterogeneous architecture (compare with Image 1) but rather are composed of simple squamous epithelium and fibrovascular islands of connective tissue (hematoxylin-eosin, x40).

Media file 7: Papillary craniopharyngiomas. Under high power, only simple squamous epithelium is seen in a papillary craniopharyngioma. The distinctive peripheral nuclear palisading, internal stellate reticulum, and nodules of "wet" keratin, which typify the adamantinomatous variant, are not seen in the papillary variant (hematoxylin-eosin, x100).

Media file 8: Rosenthal fibers in neuropils surrounding a craniopharyngioma. The brain parenchyma that surrounds both variants of craniopharyngioma is typically gliotic and often shows profuse numbers of eosinophilic Rosenthal fibers. The latter structures are composed of densely compacted bundles of glial filaments and typically are seen in astrocytic cell processes of neuropils that have been subjected to chronic compression from slowly expanding mass lesions. Rosenthal fibers are a characteristic feature of juvenile pilocytic astrocytomas (JPAs), which also may arise in the suprasellar/third ventricular region. Hence, a biopsy that samples only the surrounding neuropil of a craniopharyngioma may yield an erroneous diagnosis of JPA if the pathologist is unaware of the close association of craniopharyngioma with Rosenthal fiber formation (hematoxylin-eosin, x100).

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Keywords

adamantinoma, craniopharyngeal duct tumor, Rathke pouch tumor, craniopharyngioma, cystic tumor, Rathke cleft, epithelial-squamous calcified cystic tumor

Contributor Information and Disclosures

Author

George C Bobustuc, MD, Consulting Staff, Department of Neuro-Oncology, MD Anderson Cancer Center Orlando
George C Bobustuc, MD is a member of the following medical societies: American Academy of Neurology, American Medical Association, Society for Neuro-Oncology, and Texas Medical Association
Disclosure: Nothing to disclose.

Coauthor(s)

Morris D Groves, MD, Assistant Professor, Department of Neuro-Oncology, MD Anderson Cancer Center, University of Texas
Morris D Groves, MD is a member of the following medical societies: American Academy of Neurology, American Medical Association, and Texas Medical Association
Disclosure: Nothing to disclose.

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
Gregory N Fuller, MD, PhD is a member of the following medical societies: American Association of Neuropathologists, College of American Pathologists, International Academy of Pathology, Society for Neuro-Oncology, and United States and Canadian Academy of Pathology
Disclosure: Nothing to disclose.

Franco DeMonte, MD, FRCSC, FACS, Professor of Neurosurgery, Mary Beth Pawelek Chair in Neurosurgery, The University of Texas, MD Anderson Cancer Center, Houston Texas
Franco DeMonte, MD, FRCSC, FACS is a member of the following medical societies: Royal College of Physicians and Surgeons of Canada
Disclosure: Nothing to disclose.

Medical Editor

Amy A Pruitt, MD, Associate Professor of Neurology, University of Pennsylvania; Attending Neurologist, Hospital of the University of Pennsylvania
Amy A Pruitt, MD is a member of the following medical societies: American Academy of Neurology
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Jorge Kattah, MD, Head, Program Director, Professor, Department of Neurology, University of Illinois College of Medicine at Peoria
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Disclosure: Biogen Honoraria Consulting; Bayer Corporation Honoraria Consulting

CME Editor

Selim R Benbadis, MD, Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, University of South Florida School of Medicine, Tampa General Hospital
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Chief Editor

Tarakad S Ramachandran, MBBS, FRCP(C), FACP, Professor of Neurology, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Chair, Department of Neurology, Crouse Irving Memorial Hospital
Tarakad S Ramachandran, MBBS, FRCP(C), FACP is a member of the following medical societies: American Academy of Neurology, American Academy of Pain Medicine, American College of Forensic Examiners, American College of International Physicians, American College of Managed Care Medicine, American College of Physicians, American Heart Association, American Stroke Association, Royal College of Physicians, Royal College of Physicians and Surgeons of Canada, Royal College of Surgeons of England, and Royal Society of Medicine
Disclosure: Abbott Labs  Honoraria Consulting; Teva Marion Honoraria Consulting; Boeringer-Ingelheim Honoraria Speaking and teaching

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Long term follow up of survivors of childhood cancer. A national clinical guideline.
Scottish Intercollegiate Guidelines Network - National Government Agency [Non-U.S.].  2004 Jan.  33 pages.  NGC:003410

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