Craniopharyngioma

Background

Craniopharyngiomas are dysontogenic tumors with benign histology and malignant behavior.^{[1, 2]}  These lesions have a tendency to invade surrounding structures and to recur after a seemingly total resection (see the image below). (See Etiology and Treatment.)

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The adamantinomatous craniopharyngioma is a histologically complex epithelial lesion with several very distinctive morphologic features (hematoxylin-e....

Craniopharyngiomas most frequently arise in the pituitary stalk and project into the hypothalamus. They extend horizontally along the path of least resistance in various directions, as follows:

• Anteriorly - Into the prechiasmatic cistern and subfrontal spaces
• Posteriorly - Into the prepontine and interpeduncular cisterns, cerebellopontine angle, third ventricle,^[3]  posterior fossa, and foramen magnum
• Laterally - Toward the subtemporal spaces

The tumors can even reach the sylvian fissure. In rare cases, the tumors can develop extradurally or extracranially, developing as nasopharyngeal or pure posterior fossa craniopharyngiomas or as craniopharyngiomas extending down the cervical spine. A purely intraventricular craniopharyngioma is usually of the squamous-papillary (metaplastic) type and occurs very rarely.

Craniopharyngiomas usually present as a single large cyst or multiple cysts filled with a turbid, proteinaceous, brownish yellow material that glitters owing to the high content of floating cholesterol crystals. (See Etiology and Workup.)

Clinical behavior and the choice of surgical approach are dictated by the primary location of the tumor and its extension pattern.^[4] Prechiasmatic craniopharyngiomas (extending into the subfrontal spaces) and retrochiasmatic craniopharyngiomas (expanding into the posterior fossa) may become large before being diagnosed. (See Presentation and Workup.)

Vascular supply

The vascular supply of the tumor originates from various sources, usually all of which come from the anterior circulation. Small perforators branching from the A1 segment of the anterior cerebral artery supply the anterior portion of the tumor; lateral portions receive perforators from the proximal portion of the posterior communicating artery; and branches of the intracavernous meningohypophyseal arteries supply the intrasellar part. Craniopharyngiomas are rarely 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.

Recurrence

Recurrences usually occur at the primary site. Ectopic and metastatic recurrences are extremely rare, but 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 explains ectopic recurrences distant from the surgical bed and within brain parenchyma.

In one metastatic case, after removal of a suprasellar (adamantinomatous) craniopharyngioma, two peripheral lesions were identified seven years later, adjacent to the dura and contralateral to the initial craniotomy site. They proved to be composed of adamantinomatous tissue, raising the possibility of meningeal seeding.

In another reported case, an adamantinomatous craniopharyngioma recurred at different intervals and at different sites, along the operative track of the initial surgical procedure as well as a distant site within the brain parenchyma, suggesting that both seeding mechanisms were involved in these recurrences.

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Etiology

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

Embryogenetic theory

This theory relates to the development of the adenohypophysis and transformation of the remnant ectoblastic cells of the craniopharyngeal duct and the involuted Rathke pouch. 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 the diencephalon; the Rathke pouch is an upward invagination of the primitive oral cavity (i.e., stomodaeum).

The craniopharyngeal duct is the neck of the pouch, connecting to the stomodaeum, 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.

The 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 the stomodaeum and normally part of the adenohypophysis), which may undergo metaplasia.

Dual theory

This theory explains the craniopharyngioma spectrum, attributing the adamantinomatous type (most prevalent in childhood) to embryonic remnants, and the adult type (most commonly 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 stomodaeum and pharyngohypophyseal duct as well, such as Rathke cleft cysts, epithelial cysts, epidermoid cysts, and dermoid cysts.

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 mega bases; thus, smaller deletions and balanced alterations can be missed.^[5]

Some suggest that chromosomal imbalances^[6]  do not play a significant role in tumorigenesis of papillary and adamantinomatous craniopharyngiomas. Others report a small subset of adamantinomatous craniopharyngiomas showing a significant number of genetic alterations and abnormal deoxyribonucleic acid (DNA) copy number, thus suggesting a monoclonal origin driven by the activation of oncogenes located at specific chromosomal loci.^[7]

Adamantinomatous craniopharyngiomas have been consistently reported to show alterations in beta-catenin gene expression.^{[8, 9, 10]} 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. The Wnt signaling pathway has been proven to play a crucial role in embryogenesis and cancer. Wnt signaling is involved in the determination of cell fate, proliferation, adhesion, migration, polarity, and behavior during development. It also plays an intricate role in the temporal and spatial regulation of organogenesis.

The Wnt complex is made up of three different pathways: canonical, noncanonical, and Wnt/Ca⁺². The canonical pathway regulates cell fate determination and primary axis formation through gene transcription. The noncanonical pathway regulates cell movements through modification of the actin cytoskeleton. The 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 adamantinomatous and papillary craniopharyngiomas.

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

Furthermore, the 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.^[11]  Interferons are known modulators of Jak/STAT pathways, thus revealing the possible molecular basis for interferons as a therapeutic option in adamantinomatous craniopharyngiomas.

Some craniopharyngiomas express insulin-like growth factor receptors (IGF-1Rs) and sex hormone receptors (estrogen receptors [ERs] and progesterone receptors [PRs]).^{[12, 13]}  Despite reported sporadic expression of IGF-1R in two large, retrospective reviews (including children and adults) in which the mean treatment duration was six years and the mean follow-up period was approximately ten years, no evidence was found to suggest increased recurrence rates in patients who received growth hormone supplementation.^{[14, 15]}

ER and PR expression in one 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 have been 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.^[16]

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.

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Epidemiology

Occurrence in the United States

Data from the Central Brain Tumor Registry of the United States (CBTRUS), collected between 2009 and 2013, found the following results^{[17, 18]} :

• Overall incidence was 0.19 per 100,000 person years
• Incidence rates of craniopharyngioma for African Americans exceed those observed for Caucasian, AIAN, and API.
• Distribution by age is bimodal with one peak incidence in childhood (0-19 years) and another in adulthood between ages 45-84 years old with a higher peak for ages 65-74 years.

International occurrence

Overall, craniopharyngiomas account for 0.8% of intracranial tumors and 13% of suprasellar tumors. In the United States, the estimated incidence rate per 100,000 per year for the pediatric population (0-19 years) is 0.2, while it is 0.19 for all ages and all together 0.17-0.2 in various publications.^[19] 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.

Race-, sex-, and age-related demographics

Higher frequencies of all intracranial tumors have been reported from Africa, the Far East, and Japan; they are 18%, 16%, and 10.5%, respectively. No gender differences in incidence rate have been reported in all age groups.^[19] Craniopharyngiomas have a bimodal age distribution pattern, with a peak between ages 5 and 14 years and in adults older than 65 years, although there are reports involving all age groups.

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Prognosis

In the United States, data collected for the National Cancer Data Base (NCDB), during the periods of 1985-1988 and 1990-1992, coinciding with the introduction of computed tomography (CT) scanning, indicated that survival rates for craniopharyngioma were 86% at 2 years and 80% at 5 years after diagnosis. According to this past data, 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). Female sex has been reported as an independent predictor of increased cardiovascular, neurologic, and psychosocial morbidity.^[20]

According to the latest CBTRUS for data collected for 2009 to 2013,^[18]  survival rates were 89.5% at 2 years and 83.9% at 5 years. These results demonstrate a slight improvement when compared to data from prior decades as stated above. When comparing age groups, the 5 year survival for ages 0-14 years was 92.7%, for adolescent and young adults it was 88.1% and for adults after the age of 40 years old it was 77.7%.^[18] Patients with craniopharyngiomas have overall mortality rates higher than the general population.

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History

Craniopharyngioma typically is a slow-growing tumor. Symptoms frequently develop insidiously and usually become obvious only after the tumor attains a diameter of about 3cm. The time interval between the onset of symptoms and diagnosis usually 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 related to hypothyroidism (i.e., weight gain, fatigue, cold intolerance, constipation). Almost 25% have associated signs and symptoms of adrenal failure (i.e., orthostatic hypotension, hypoglycemia, hyperkalemia, cardiac arrhythmias, lethargy, confusion, anorexia, nausea, and vomiting), and 20% have diabetes insipidus (i.e. excessive fluid intake and urination). Most young patients present with growth failure and delayed puberty.^[21]

As disease progress, 80% of adults complain of decreased sexual drive, and almost 90% of men complain of impotence, while most women complain of amenorrhea.

Optic pathway dysfunction is noted in 40-70% of patients on presentation. Children rarely become aware of visual problems (only 20-30%) and often present after almost complete visual damage becomes irreversible. The manifestation of optic pathway dysfunction usually varies from papilledema to visual field deficits and even optic nerve atrophy in severe cases.

Other manifestations relate to the various connections of the hypothalamic-pituitary complex and surrounding structures. When the thalamus, hypothalamus and frontal lobes are affected, patients experience endocrine, autonomic, and behavioral problems (i.e. hyperphagia and obesity, psychomotor retardation, emotional immaturity, apathy, short-term memory deficits, incontinence).^[22]  Short stature is present in 23-45% of patients, and obesity affects 11-18% of patients.^[23]

The following relationships are seen between the anatomic location of the craniopharyngioma and major clinical syndromes:

• Prechiasmal localization - Typically results in associated findings of optic atrophy (i.e., progressive decline of visual acuity, constriction of visual fields). The chiasm stretches and gets displaced away from the optic nerve, which eventually causes vascular deprivation of the nerves and damage to nerve fibers.
• Retrochiasmal location - Commonly is associated with hydrocephalus with signs of increased intracranial pressure (i.e. papilledema, horizontal double vision). The tumor compresses the floor of the third ventricle and can lead to obstruction of CSF flow through the Foramen of Monroe.
• Intrasellar craniopharyngioma - Usually manifests as headache and/or endocrinopathy.

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Physical Examination

Neurologic and general examinations are both indicated.

Neurologic examination

Signs suggestive of increased intracranial pressure—horizontal double vision (unilateral/bilateral) and papilledema (unilateral/bilateral)—should be sought for 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 (i.e., compression) of the optic chiasm and/or tracts. Formal visual field testing by ophthalmology is recommended as part of the initial work up and serial testing can be used in follow up to monitor tumor growth/recurrence.

General examination

Signs and symptoms may be related to various endocrinopathies.

Hypothyroidism

Symptoms of hypothyroidism include the following:

   ▪     Puffiness and non-pitting edema

   ▪     Slow return phase of deep tendon reflexes

   ▪     Hypoventilation and decrease in cardiac output

   ▪     Pericardial and pleural effusions

   ▪     Constipation

   ▪     Anemia – i.e., normochromic normocytic anemia

   ▪     Decreased mental function

   ▪     Psychiatric changes

Cortisol-related deficiency 

The signs and symptoms of cortisol deficiency include the following:

• Hypotension, which is often orthostatic
• Gastrointestinal symptoms, which include anorexia, nausea, and vomiting
• Weight loss
• Hypoglycemia
• Lethargy
• Confusion
• Psychological disturbances, i.e.. psychosis and intolerance to stress

Changes in volume and sodium control

The signs and symptoms of aldosterone deficiency include the following:

   ▪     Hypovolemia

   ▪     Decreased cardiac output

   ▪     Decreased renal blood flow with azotemia

   ▪     Fatigue

   ▪     Weight loss

   ▪     Cardiac arrhythmias due to hyperkalemia

Compression of the infundibulum can lead to the common presentation of diabetes insipidus.

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Approach Considerations

The diagnostic evaluation of craniopharyngioma includes high-definition brain imaging. Brain MRI with and without contrast is the gold standard. The use of computed tomography (CT) scan is optional and can show the common calcifications that can be seen in these tumors. However, it is important to note that a CT is not specific enough as a standalone diagnostic test. The use of vascular imaging, such as MR angiography (MRA) or CTA, is decided on a case-by-case basis typically for surgical planning or when a possible vascular malformation is speculated. Complete endocrine evaluation with appropriate laboratories, neuro-ophthalmologic evaluation with formal visual field documentation, and neuropsychological assessment are crucial in these patients.

MIB-1 labeling index

The MIB-1 labeling index is a measure of the disease’s proliferative activity. It is determined by using an immunohistochemical method with monoclonal antibody MIB-1 and may be useful for the planning of adjuvant therapy. One study reported that an MIB-1 labeling index of greater than 7% predicted regrowth/recurrence.

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Endocrinologic Studies

Assessment of endocrine function requires 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 pediatric as well as 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 correlate various neurohormonal deficits with neuropsychological deficits.

In emergent cases, hormonal testing should be limited to diagnosing diabetes insipidus, hypoadrenalism, and hypothyroidism, as these hormones require the initiation of treatment prior to surgery.

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Imaging Studies

Imaging studies can strongly suggest the diagnosis of craniopharyngioma. The radiologic hallmark of a craniopharyngioma is the appearance of a sellar/suprasellar calcified cyst. Note panels A-C in the image below.

About 80-87% of craniopharyngiomas are calcified and 70-75% are cystic. Calcifications are more common in children (90%) than in adults (50%).

CT scanning is the most sensitive method for demonstrating calcifications as high-density areas and has replaced the use of plain radiographs. In recent years the use of susceptibility weighted imaging (SWI) in MRI gained popularity, so imaging workup today may be limited to an MRI only, without the need for a CT scan. Note panel C in the image below. 

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T1-weighted MRI with gadolinium in sagittal (A) and coronal (B) views demonstrates the cystic nature of a craniopharyngioma. The calcified component i....

Cyst content usually has the same density as cerebrospinal fluid (CSF). Contrast administration better delineates 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. Note panels A-C in the image below.^{[24, 25]}

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T1-weighted MRI with gadolinium reveals a large cystic craniopharyngioma in sagittal (A), axial (B), and coronal (C) views. There is associated elevat....

MRA is used as needed on a case by case basis, either for eliminating the possibility of vascular lesion or for visualizing the major cerebral vessels and their relation to the tumor. It has largely replaced the 6 and 4-vessel angiogram.

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Histologic Findings

The histologic spectrum of craniopharyngioma includes three main types: adamantinomas, papillary craniopharyngiomas, and mixed tumors.

Adamantinoma

Adamantinomas consist of reticular epithelial masses that resemble the enamel pulp of developing teeth. This is seen predominantly in children. Distinctive features include a palisading basal layer of small cells enclosing a loose, stellate reticular zone, as well as areas of compactly arranged squamous cells. Adamantinomas contain nodules of keratin ("wet" keratin), which are the hallmarks of this tumor subtype. (See the images below)

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The adamantinomatous craniopharyngioma is a histologically complex epithelial lesion with several very distinctive morphologic features (hematoxylin-e....

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

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Adamantinomatous craniopharyngiomas. Frequently, the inner epithelium beneath the superficial palisade undergoes hydropic vacuolization and is referre....

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Adamantinomatous craniopharyngiomas. Another distinctive feature of the adamantinomatous variant is scattered nodules of keratin. These nodules are re....

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Adamantinomatous craniopharyngiomas. Nodules of "wet" keratin frequently calcify; in aggregate, this calcification often can be detected on CT scans a....

Papillary craniopharyngioma

The squamous papillary craniopharyngioma contains islands of squamous metaplasia embedded in a connective tissue stroma, with infrequent cystic degeneration and calcification. This subtype is rarely seen in children and does not form keratin nodules. (See the images below)

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Papillary craniopharyngioma. In contrast to the adamantinomatous variant, papillary craniopharyngiomas do not show complex heterogeneous architecture ....

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Papillary craniopharyngiomas. Under high power, only simple squamous epithelium is seen in a papillary craniopharyngioma. The distinctive peripheral n....

Brain parenchyma

The brain parenchyma that surrounds both variants of craniopharyngioma is typically gliotic and often has profuse numbers of eosinophilic Rosenthal fibers. These fibers contain densely compacted bundles of glial filaments and are typically seen in astrocytic cell processes of neuropil that has been subjected to chronic compression from slowly expanding mass lesions. (See the image below)

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Rosenthal fibers in neuropils surrounding a craniopharyngioma. The brain parenchyma that surrounds both variants of craniopharyngioma is typically gli....

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Approach Considerations

Essentially, two main management options are available for craniopharyngiomas: (1) attempt a gross total resection or (2) perform a planned subtotal resection followed by radiotherapy or some other adjuvant therapy.

No firm consensus exists concerning the appropriate management of craniopharyngiomas, and no guidelines have been established yet.

Most of the accepted management strategies are from retrospective reviews; no prospective, randomized clinical trials have been conducted to compare the various therapeutic modalities.

Although no consensus exists, most authors maintain that successful management is determined by the ability to preserve independent social functioning, prevent symptomatic recurrence, and increase survival rate.

Neuropsychological deficits represent the major limiting factor for independent social functioning because (1) patients often can overcome minor neurologic deficits and (2) hormone replacement therapies are widely available. The degree of psychosocial impairment correlates directly with the degree of hypothalamic injury sustained at the time of surgery.

There has been significant debate in recent years regarding the outcomes of GTR (Gross total removal) in the pediatric population given the high risk for hypothalamic injury and deficits, which can be life-altering in children (i.e., extreme obesity, deterioration in educational abilities).

Attempts at employing systemic chemotherapy in the treatment of craniopharyngiomas have been unsuccessful. Systemic biologic therapies currently under investigation include interferon (IFN) alpha-2a for progressive or recurrent craniopharyngiomas, with promising results.

Inflammatory cytokines and biomodulation

Several inflammatory cytokines have been shown to be elevated in the craniopharyngioma cyst fluid in comparison to CSF. Interleukin (IL)–1alpha and tumor necrosis factor (TNF)–alpha levels may be significantly elevated. The concentration of IL-6 may be over 50,000 times greater in the cystic fluid than in the CSF.^[26]  These findings support the hypothesis that biomodulation of the cytokine profile can lead to prolonged stability and even tumor regression.

IFN-alpha exerts diverse influences mainly on cytokine antagonists and soluble adhesion molecules. It has been shown to play a role in the treatment of craniopharyngioma after systemic as well as local, direct intracystic delivery.^[27]

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Follow-up

Postsurgical follow-up should be planned in 1-2 weeks for all patients. Patients with subtotal resections who are candidates for radiation therapy should start radiation usually 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. Strict follow-up is advised.

Each follow-up visit should include a brain MRI to be used for comparison with previous films and to correlate imaging with the clinical exam and neurocognitive testing results. Neuroendocrine and neuroophthalmology status should be followed up as well.

Neurocognitive testing must be considered for preoperative and postoperative patients, as well as patients who have undergone subtotal resection followed by radiation. All patients should have neurocognitive testing if performance at school or workplace drastically declines or clinical examination reveals worsening neurocognitive deficits (i.e., problem solving, language, memory, apraxia).^{[22, 28]}

In some patients, deficits encountered are related to radiation injury. These are identified by specific MRI findings and correlated with neurocognitive testing results. Subsequently, specific treatments can be used. Close monitoring of endocrine dysfunction as evidenced by symptoms and confirmatory laboratory tests are recommended for all patients. Most patients require multiple hormonal supplements and adjustments during their postsurgical/postradiation phase and even years later.

Preventive management of long-term and multisystem morbidities is key for a successful outcome. A comprehensive multidisciplinary approach is strongly recommended. Panhypopituitarism was reported in almost 90% of patients followed for more than 10 years. Long-term follow-up with endocrinology is strongly recommended.

Other prevalent morbidities include neurologic (49%), psychosocial (47%), and cardiovascular (22%) abnormalities. The female sex is reported as an independent predictor of increased cardiovascular, neurologic, and psychosocial morbidity. Long-term follow-up should include appropriate hormonal replacement^[29]  (including estrogen in premenopausal women) and aggressive control of cardiovascular risk factors (blood pressure, weight, lipids, and glucose). 

Other prevalent morbidities include neurologic (49%), psychosocial (47%), and cardiovascular (22%) abnormalities. The female sex is reported as an independent predictor of increased cardiovascular, neurologic, and psychosocial morbidity. Long-term follow-up should include appropriate hormonal replacement^[29] (including estrogen in premenopausal women) and aggressive control of cardiovascular risk factors (blood pressure, weight, lipids, and glucose).

Recurrence

Immunohistochemical studies and case reports suggest higher incidence of recurrence in patients receiving growth hormone and/or sex hormone replacement, as some craniopharyngiomas express insulin-like growth factor receptors (IGF-1Rs), estrogen receptors (ERs), and progesterone receptors (PRs).

Despite the sporadic expression of IGF-1Rs, two large retrospective reviews assessing children and adults, in which the mean treatment duration was 6 years and the mean follow-up was 10 years, reported no evidence of increased recurrence rates in patients who received growth hormone supplementation.^{[14, 15]}  Imaging follow-up every 4-6 weeks and close clinical monitoring are indicated with sex hormone and/or growth hormone replacement.^[30]

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Nonsurgical Management

Agents/modalities used in the treatment of craniopharyngioma include (1) radiation therapy applied as external fractionated radiation, stereotactic radiation, or brachytherapy (intracavitary irradiation)^{[31, 32, 33, 34, 35]} and (2) bleomycin for local intracystic chemotherapy.^{[36, 37, 38]}

Radiation therapy

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

Proton beam radiation

This radiation modality became more and more common in recent years for this kind of tumor, mainly because of the Bragg peak effect, which means the energy beam peak occurs immediately before the particles come to rest. In a review published by Bishop and colleagues,^[39] they didn’t find any difference between conformal photon radiotherapy and proton beam therapy in terms of overall survival and solid and cystic control among pediatric population with craniopharyngioma.

External fractionated radiation

This offers a dual advantage by (1) allotting normal cells more time for repair and (2) amplifying a higher cumulative effect of DNA damage in more rapidly dividing tumor cells.

Radiation following a partial resection offers excellent long-term results (80% at 20 years). When compared, the results of giving radiation after partial resection are superior to those achieved when radiation is delayed until the time of recurrence. Recurrence is less frequent after imaging-confirmed total resection (10-30% recurrence rate), in which case, radiation should be delayed.

Stereotactic radiation

Stereotactic radiation has been used primarily as first-line of treatment for rapidly expanding or symptomatic, solid, and small craniopharyngiomas (< 25-30 mm in diameter). Stabilization or reduction of the cystic cavity after radiosurgery is achieved in more than 60% of patients.^[40]

Stereotactic radiation has also been used for further treatment of residual solid tumor after brachytherapy.

Brachytherapy/radioisotopes

Brachytherapy is recommended for solitary cystic craniopharyngiomas and consists of stereotactic aspiration of cystic content followed by instillation of beta-emitting isotopes (ie, phosphorus 32, rhenium 186, gold 198, yttrium 90).

Brachytherapy is highly feasible because about 60% of craniopharyngiomas occur as single large cysts. Early refilling is common, requiring intermittent aspiration either by stereotactic puncture or Ommaya reservoir.

Intracystic chemotherapy

Intracystic injection of bleomycin^[41]  and internal irradiation with radioisotopes have been reported to control the tumor cysts, yet numerous side effects have been described.^[42]

Antibiotic with anti-tumor activity: Bleomycin

Bleomycin is a mixture of glycopeptides extracted from the Streptomyces species. There is ongoing research regarding the utility and toxicity of using intracystic bleomycin, especially in the pediatric population. For nearly 30 years, bleomycin has consistently demonstrated objective tumor response and disease control in 20% to 50% of patients.^[43] In 2016, a Cochrane database review summarized that a conclusion cannot be made because there is not enough high-quality data regarding this treatment as a whole and especially among kids.^[44]

In combination with other drugs, chemotherapeutic agents are used frequently and systemically against epithelial tumors. In the early 1970s, bleomycin was shown to effectively inhibit craniopharyngioma tissue growth in vitro. Intracavitary bleomycin reduces cyst size and thickens the cyst wall, facilitating surgical excision of the cystic membrane, which may otherwise fragment at the time of surgery. However, reports of intracystic bleomycin use are limited.

The toxicity of bleomycin depends on the age of the patient and the cumulative dose of the drug. Systemic administration may cause pneumonitis, which can progress to fatal pulmonary fibrosis.

When administered systemically, bleomycin does not produce significant bone marrow toxicity. Toxicity with local administration results from systemic contamination (associated with anaphylactoid reaction, transient fever, nausea, and vomiting) and leakage into surrounding neural tissue.

Fatal outcomes have been reported with leakage, related to diffuse diencephalon and brainstem edema. Transient local toxicity involving the surrounding brain parenchyma may be reversible with high-dose steroids.

Alpha interferon

This is another potential intracystic treatment modality. Few publications in the past showed a good response in some of the cases, but research is still ongoing. The literature states that fatigue is the most frequent side effect and the main limiting factor of alpha interferon treatment.^[45] The efficacy of alpha interferon against squamous cell carcinoma of the skin, in which it induces apoptosis, is well established.^[46] Jakacki et al.^[47]  was the first group to use systemic alpha interferon in the treatment of either recurrent disease or patients with craniopharyngioma that did not respond to conventional therapy. This study was a phase II study with a small cohort of pediatric patients (less than 20 years of age), and they were able to show that for patients that had a predominantly cystic lesion the response to treatment was very good. However, all the patients experienced episodes of fever in the first weeks of treatment, as well as muscle cramps and myalgia, and almost 50% of the patients developed significant signs and symptoms of alpha interferon toxicity, which led to either the interruption of treatment or a reduction in the doses administered. This treatment’s benefit, safety, and long-term efficiency is yet to be determined.

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Surgery

There are a variety of microsurgical and endoscopic approaches that can be applied to craniopharyngiomas. There is an ongoing debate as to weather the neurosurgeon should even attempt a gross total resection, or just perform a biopsy and decompression of the tumor (usually the cyst) followed by a referral for adjuvant radiotherapy. The major surgical approaches to craniopharyngiomas can be summarized into five categories: (1) anterolateral transcranial, (2) midline transcranial, (3) extended endoscopic endonasal, (4) intraventricular, and (5) lateral transcranial. While each approach has its advantages and limitations, an individualized approach tailored to each patient based on multiple factors is crucial in determining the optimal treatment strategy. Nowadays, the best treatment can be achieved in facilities where knowledge and expertise in both microsurgical and endoscopic endonasal techniques are present, and the specific approach or combination can be tailored to each patient.^[48]

Gross total resection

Gross total surgical resection has traditionally been the treatment of choice for craniopharyngiomas. Note panels A and B in the image below.

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Coronal views of T1-weighted MRI for a patient with craniopharyngioma before gross total resection (A) and at postoperative follow-up evaluation (B). ....

There are several surgical approaches, as mentioned above. Different considerations are important when choosing the approach for a specific case, including size of the lesion, extension to nearby anatomical structures (i.e., temporal lobes, 3^rd ventricle, vascular structures, etc.), amount of parenchymal edema, and more.

Local inflammation can lead to tumor adhesion to surrounding vascular structures. Tumor adhesion 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 due to injury to the vasa vasorum leading to weakening of the adventitia.

For many years, complete resection was considered the treatment of choice for optimal tumor control and lower recurrence rates. More recent studies have suggested that a tissue-sparing (yet aggressive) near-total resection followed by radiotherapy may be a suitable alternative to gross total resection, as the rates of tumor control are similar, but the risk of endocrine and behavioral morbidity is less than with more aggressive surgery. Many investigators have associated very aggressive attempts at total tumor removal with significant endocrinopathies. Permanent diabetes insipidus occurs in 68-75% of adults and 80-93% of children. Panhypopituitarism occurs in 75-100% of patients who undergo resection, and replacement of two or more of the anterior pituitary hormones is necessary in 80-90% patients. Hypothalamic obesity occurs in 40-50% of patients postoperatively.

A list of potential perioperative morbidities includes the following:

• Seizures
• Visual deficits (including blindness)
• Hypothalamic injury
• Stroke
• Cerebrospinal fluid (CSF) leakage

Craniopharyngiomas have a high rate of recurrence, mostly in the first three years after surgery. Overall, recurrence rates range from 0-17% after gross total resection and from 25-63% after subtotal resection with radiotherapy. However, two studies have reported recurrence rates of 53-62% even after apparent complete removal of the tumor. One series assessed only pediatric patients and the other included patients younger than 25 years. Therefore, young age may be a risk factor for tumor recurrence independently of the degree of tumor excision. Ultimately, if left untreated, these recurrences may cause death through aggressive local behavior.

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Limited Surgery and Radiotherapy

Recent studies propose subtotal resection with postoperative radiotherapy as the management paradigm of choice for craniopharyngiomas, especially in the pediatric population. Goals of this approach include pathologic confirmation of the tumor and surgical decompression of the optic chiasm. Surgery is followed either by proton beam radiotherapy or by external beam radiation, at a dose of 5400-5500 cGy delivered at 180 cGy/fraction. More advanced radiotherapy modalities currently under investigation include Gamma Knife and CyberKnife radiosurgery.^{[49, 50]}  As mentioned above, in 2014, Bishop and colleagues compared the efficacy and safety of postoperative radiation therapy for two modalities – proton beam therapy (PBT) and intensity-modulated radiation therapy (IMRT).^[39] In their work, they didn’t find any significant difference between the two groups, although the follow-up time for the PBT was much shorter. Interestingly enough regarding the tumoral cyst, they found that during therapy, 40% of patients had cyst growth (20% requiring intervention), a third of the patients had cyst growth immediately after therapy and that was seen more commonly in the IMRT group. Toxicity did not differ between the two groups. Their final conclusion did not find any significant difference between these two modalities and they recommended that in any case strict follow-up needs to be done in regards to cyst dynamics. 

The incidence of tumor progression after subtotal surgical resection and radiotherapy ranges from 12-25% and is similar to rates associated with failed gross total resection and radiotherapy (4-25%).

Radiotherapy delivered after recurrence (salvage radiotherapy) is effective, with a posttreatment progression rate of 29%. Recurrence following radiotherapy has been associated with a 50-80% mortality rate.

Complete surgical removal of craniopharyngiomas can be achieved with reasonable safety in the majority of patients. Aggressive attempts at total tumor removal may lead to increased rates of anterior hypopituitarism, diabetes insipidus, growth disturbances, and behavioral and feeding abnormalities. On the other hand, subtotal resection with adjuvant radiotherapy can provide tumor control rates essentially similar to those for gross total resection while limiting hypothalamic and hypophyseal morbidity.

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Other Surgical Considerations

For selected patients with suprasellar craniopharyngiomas, an extended endonasal endoscopic approach could provide a viable alternative to transcranial approaches.^{[51, 29, 52]}

Other approaches that can be useful in the management of giant craniopharyngiomas, especially at the time of recurrence, include (1) intermittent aspiration by stereotactic puncture or Ommaya reservoir placement, (2) intracystic injection of bleomycin,^[41]  and (3) internal irradiation with radioisotopes. The latter two treatment modalities have been reported to control the tumor cysts in 90-100% of cases.

Another important consideration, especially with suprasellar tumors, is the need for CSF diversion (i.e., ventriculoperitoneal shunt). 

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Future Treatment Considerations

There is data supporting the suspicion clinicians have had for a long time that adamantinomatous and papillary craniopharyngioma (AC and PC, respectively) are different entities and hence may respond to different treatment modalities. Analyses of the craniopharyngioma genome and transcriptome as well as analysis of the DNA methylation patterns of craniopharyngiomas have provided considerable insight into the origin of these tumors and into what drives their growth.^[48]

Adamantinomatous craniopharyngioma

The main pathway under investigation in this subgroup is that of β-catenin and the WNT/Wingless Pathway. β-catenin is a key member in the WNT pathway. The CTNNB1 gene encodes this protein and it plays a critical role in development, cellular proliferation, differentiation, and cell migration.^{[53, 54, 55]}

When WNT pathway is activated, an intracellular signaling cascade starts that ultimately prevents formation of the β-catenin destruction complex 31. Without the destruction complex, the β-catenin protein accumulates within the cell, binding another protein called fascin and ultimately changing the genomic transcription and facilitating uncontrolled cellular proliferation.^{[56, 57]} The accumulation of β-catenin eventually can reduce E-cadherin expression, which may reduce cell adhesion and results in cells that are more motile, which eventually can lead to increased invasive potential. Researchers are looking at the possible inhibition of either fascin or β-catenin accumulation that could potentially lead to re-activation of the destruction complex, preventing the progression of the cell towards uncontrolled proliferation and cell migration.

Nuclear accumulation of β-catenin results from mutations within exon 3 of the CTNNB1 gene. While mutations have been identified at a number of different codons, these all affects the binding of GSK3b.^{[56, 58, 59, 9]} As a result of this mechanism, nuclear accumulation of β-catenin is a histological hallmark of CTNNB1 mutation.^{[53, 54, 60]} Interestingly enough, when examining AC for this specific mutation, it is very common and happens at a rate higher than 70% of the cases.^{[61, 62]} The clinical implications of this knowledge have yet to be discovered and developed.

The Sonic hedgehog (SHH) pathway plays an integral role in the maintenance of adult stem cells and in the normal development of several organs, including the pituitary gland and Rathke’s pouch. It has been linked to different pathologies in the brain including medulloblastoma, basal cell carcinoma, and even meningiomas.^{[63, 64]} The therapeutic relevance of SHH protein can be significant since it is highly unregulated in AC, even in comparison to other brain tumors, especially in the pediatric population.^[62]  This raises the possibility of the inhibition of SHH pathway as a clinical tool for treating AC. Preclinical animal studies of the smoothened inhibitor vismodegib are ongoing.^[65] SHH expression opens up the possibility for better understanding of the difference between AC and PC, since as Hölsken and colleagues^[66]  demonstrated, there is a significant difference in the expression of SHH protein between them, with AC tumors having high overexpression. The identification of cilia throughout the epithelium of AC also further intensifies the link to the subgroup of tumors of SHH that have cilia as well (i.e., Medulloblastoma). This again is a potential treatment path for AC.^[67]

Epidermal growth factor has been described in a variety of tumors, as well as the clinical implications for its inhibition. It has been described as factor that promotes cell growth and infiltration. In AC, we can see downstream upregulation of this pathway. This pathway is usually regulated by the epidermal growth factor receptor (EGFR).^[68] The involvement of EGFR in the regulation of the expression of stem cell markers in AC, and the presence of the activated EGFR pathway in β-catenin accumulating cells, suggests a potential role for inhibition of the cell proliferation and migration through this pathway. As for now, the study is ongoing.

For AC, there is a robust amount of ongoing research as was described for the pathways mentioned above and many others (such as the use of Dasatinib as part of inhibition of tyrosine kinase pathway).^[65]

Papillary craniopharyngioma

A possible treatment of PC has the potential of changing the role of neurosurgeons in treating this subtype of craniopharyngioma, which usually affects adults. In PC, in contrast to AC, β-catenin localizes to the cell membrane, similar to the pattern of localization in other CTNNB1 wild-type tumors of the sellar region^{[56, 54]}  and throughout the body.^{[65, 48]} The most distinct pathway in PC is MAP kinase. Brastianos and colleagues identified the BRAFv600e mutation in 92.8% of PC specimens.^[69] Later publications found incidence rate to be close to 100%.^{[70, 71]} This revealed the potential for a diagnostic tool and BRAF inhibitors as a possible effective treatment. BRAF mutation upregulates MAP kinase signaling and propagate cell division and proliferation. This mutation was found to have multiple subtypes in a variety of tumors with the most known being substitution of valine by glutamate at codon number 600, termed the BRAFv600e mutation. In terms of diagnosis, recognition of BRAF v600e mutation in a sellar mass can help differentiate PC from other potential diagnoses.^{[71, 72, 48]} In a subset of PC, there is a combination of the genomic mutation CTNNB1 and the BRAF mutation. Several publications describe a very good response to BRAF inhibitor (i.e., vemurafenib), MEK inhibitor (trametinib) and RAF inhibitor (dabrafenib). One interesting point regarding the inhibition of either BRAF or MEK/RAF cycle is that, like with gliomas, when the treatment is stopped, the tumor tends to recur and sometimes will not respond again for the same treatment. The significant reduction in the size of the tumors and the cystic component after the treatment raises the possibility of using tool in the future as a neoadjuvant treatment before surgery or as an adjuvant treatment after the first surgery and before a second one if needed.

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Medication Summary

Agents/modalities used in the treatment of craniopharyngiomas include (1) radiation therapy applied as proton beam radiation or external fractionated radiation, stereotactic radiation, or brachytherapy (intracavitary irradiation),^{[31, 32, 33, 34, 35]}  (2) bleomycin for local intracystic chemotherapy,^{[36, 37, 38]}  and (3) possible new targeted treatments that arise from the vast ongoing molecular research

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Class Summary

In combination with other drugs, chemotherapeutic agents 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. Other agents like interferon alpha are being tested.

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Class Summary

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. Several radiation modalities are being used for the treatment of craniopharyngioma, including proton beam treatment, external fractionated radiotherapy, stereotactic raditherapy, and more.

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