Craniopharyngioma

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Practice Essentials

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. 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.

Signs and symptoms

The time interval between the onset of symptoms and diagnosis usually ranges from 1 to 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.

Diagnosis

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.

Management

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.

Agents/modalities used in the treatment of craniopharyngioma include (1) radiation therapy applied as external fractionated radiation, stereotactic radiation, or brachytherapy (intracavitary irradiation)[3, 4, 5, 6, 7] and (2) bleomycin for local intracystic chemotherapy.[8, 9, 10]

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.) Craniopharyngiomas are classified as grade I lesions in the most recent WHO classification of tumors with two different tumor types: adantinomatous and papillary. These two entities are now recognized as different tumors and no longer described as subtypes of the same lesion. Their molecular characterization as well as the differences regarding prognosis, imaging, and treatment prompted this separation for their individualized analysis and management. (See Approach Considerations.)



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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:

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.[12] 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.

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.[13]

Some suggest that chromosomal imbalances[14]  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.[15]

Adamantinomatous craniopharyngiomas have been consistently reported to show alterations in beta-catenin gene expression.[16, 17, 18] 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.[19]  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]).[20, 21]  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.[22, 23]

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.[24]

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.

Epidemiology

Occurrence

Data from the Central Brain Tumor Registry of the United States (CBTRUS), collected between 2016 and 2020 (corresponding to the 2023 report),[25] found the following results:

Overall, craniopharyngiomas account for 0.5% 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 (0–14 years) is 0.2, while it is 0.13 for ages 15–39 years. Incidence reaches up to 0.22 for patients older than 40 years.  

Race-, sex-, and age-related demographics

There is an increased incidence in Black patients versus White patients (0.26 vs 0.17 cases per 100,000 people). No differences are seen between Hispanic and non-Hispanic people. A higher five-year total incidence was observed in males compared to females (1102 cases vs 987 cases).[25]

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. 

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.[26]

According to the latest Central Brain Tumor Registry of the United States (CBTRUS), for data collected during 2016–2020, survival rates were 92.5% at 1 year and 84.9% at 5 years. These results demonstrate a slight improvement when compared to data from prior decades, as stated above.[25]

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.[27]

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).[28]  Short stature is present in 23-45% of patients, and obesity affects 11-18% of patients.[29]

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

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:

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.

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.

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.

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.[30, 31]



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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.

Histologic Findings

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

Adamantinoma

In adamantinomas, the epithelium is well differentiated and typically presents with different morphology as chords, lobules, and ribbons. Fibrosis and calcifications are common. 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. (See the images below). Cystic structures lined with flat epithelium are often seen sparsed between wet keratin nodules. Invading protrusions into normal brain parenchyma are often seen. 

Malignant features are very rare, often due to multiple recurrences and radiation. 

There is P63-positive expression in all the layers of the epithelium. SOX9 and PDL1 are expressed in the epithelial lining of cystic structures. Cytokeratins (CK) 5, 6, 7, 17, and 19 are commonly expressed. CK8 and 20 expression can be absent; however, these markers are typically expressed in other lesions such as Rathke cleft cysts.[32]  Ki67 can be expressed in palisading regions, however, its presence is inconstant and has no prognostic factor. CTNNB1-activating mutations are typical of adamantinomatous tumor.[33]



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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 non-keratinizing squamous papillary craniopharyngioma contains islands of squamous metaplasia embedded in a fibrovascular ciliated tissue stroma, with infrequent cystic degeneration and calcification. This lesion is rarely seen in children and does not form keratin nodules. (See the images below.) Calcifications and palisadings are absent. T cells and macrophages are often seen infiltrating the tumor as well as goblet cells within the epithelium. Expression of BRAFp.V600E mutations is an important hallmark to distinguish papillary tumor from the adamantinoumatous type, as the latter do not correlate to this mutation. Molecular detection of BRAF mutations should be performed in all cases if suspicion of papillary craniopharyngioma is high.[33]



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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....

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.

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 (ie, extreme obesity, deterioration in educational abilities).

As data have elucidated 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, new tendencies regarding surgical goals have emerged. Nowadays, treatment modalities for craniopharyngiomas radicate within two main options: total resection versus subtotal resection with adjuvant radiotherapy. 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. However, subtotal resection with adjuvant radiotherapy can provide tumor control rates essentially similar to those for gross total resection while limiting hypothalamic and hypophyseal morbidity. 

Understanding the difference in molecular biology of these lesions may lead the clinician to follow distinct approaches.

Adamantinomatous craniopharyngioma (AC)

The main pathway 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.[34]

When the 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.[35, 36]  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. The possible inhibition of either fascin or β-catenin accumulation 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 affect the binding of GSK3b.[35, 37, 38, 17]  As a result of this mechanism, nuclear accumulation of β-catenin is a histological hallmark of CTNNB1 mutation.[39, 40, 41, 33]

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.[42, 43]  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.[44]  Preclinical animal studies of the smoothened inhibitor vismodegib have been carried out; however, evidence points out detrimental effects of this therapy in ACs with diminished mean survival and protumorigenic effects.[45, 46]  

Epidermal growth factor has been described in a variety of tumors, as has the clinical implications of its inhibition. It has been described as a 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).[47]  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 cell proliferation and migration through this pathway. EGFR inhibitors are under investigation as they may sensitize residueal tumors to radiation.[48]

Papillary craniopharyngioma (PC)

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[35, 40]  and throughout the body.[45, 49]  The most distinct pathway in PC is MAP kinase. Brastianos et al identified the BRAFv600e mutation in 92.8% of PC specimens.[50]  Later publications found incidence rate to be close to 100%.[51, 52]  This revealed the potential for a diagnostic tool and BRAF inhibitors as a possible effective treatment. BRAF mutation upregulates MAP kinase signaling and propagates 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.[52, 53, 49]  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 (ie, 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 to 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.[33]

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 more than 50,000 times greater in the cystic fluid than in the CSF.[54]  These findings support the hypothesis that biomodulation of the cytokine profile can lead to prolonged stability and even tumor regression. Similarly, evidence has pointed out the role of glioma-associated oncogene family zinc finger 1 (GLI1) of the SHH pathway in AC, promoting the uprise of IL-6 and subsequent augmentation in the inflammatory response and favoring tumor progression. In vivo experiments have been carried out exhibiting induction of tumor progression and inflammatory responses through overexpression of GLI1. In contrast, GLI1 downregulation showed opposite effects.[55, 33]

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.[56]

Complete Resection versus Limited Surgery and Radiotherapy

The optimal treatment for craniopharyngiomas is a subject of ongoing debate, as the different types of treatments have different complications. However, new targeted therapies for specific mutations in the different tumors has prompted a paradigm shift in the surgical approach to these lesions. Targeted therapies for papillary craniopharyngiomas (PCs) with BRAF V600E mutations have demonstrated optimal responses; therefore, complete and aggressive resection might not be ideal if targeted therapies are available. In contrast to the papillary subtype, adamantinomatous craniopharyngiomas with WNT/CTNNB1 mutations have shown suboptimal response to therapies targeting these pathways.[57]

Each patient should be properly examined to choose a tailored approach according to clinical suspicion. Variables involved in the decision include the molecular biology of the tumor, size and proximity to other anatomical and vital structures such as neurovascular structures, arachnoid adhesions, the hypothalamus, and surrounding brain parenchyma. Complications regarding adjuvant therapies should be considered as well.[57]

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). ....

Different considerations are important when choosing the approach for a specific case, including size of the lesion, extension to nearby anatomical structures (ie, temporal lobes, 3rd ventricle, vascular structures, etc.), amount of parenchymal edema, and more.

Local inflammation can lead to tumor adhesion to surrounding vascular structures. Tumor adhesion and calcified capsules represent the most common causes 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. Unlike other CNS tumors, GTR in craniopharyngiomas is a poor predictor of success regarding survival and comorbidities. Hypothalamic involvement urge to a less aggressive approach for the preservation of endocrinologic and neurocognitive functions. 

A list of potential perioperative morbidities includes the following:

Subtotal resection (STR) and radiotherapy

With the emergence of targeted therapies, there has been a growing tendency towards subtotal resection or cyst reduction followed by adjuvant radiotherapy. This approach comes with less  comorbidities and complications (endocrine abberancies, visual impairment, etc.) with similar control rates of the disease.

Evidence shows no differences in overall survival of pediatric patients undergoing GTR versus patients undergoing STR followed by radiotherapy. However, survival is reduced in patients undergoing STR only compared with patients undergoing STR and radiotherapy.[58] As such, this does not justify a more agressive approach with greater chances of permanent damage. As targeted therapies still lack optimal results in AC, preliminary biopsy to identify molecular status of the lesion could be performed. Similarly, radiomic features have been described, successfully discriminating AC from PC.[59]

Proton beam radiation or proton beam therapy (PBT) has become 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 contrast to photon radiotherapy, proton beam radiation focuses on the targeted lesion, reducing surrounding brain irradiation and thus further reducing toxicity. Studies reported a 5-year overall survival up to 97% of patients undergoing PBT. However, this value dropped to 60% in some studies in patients with multiple resections. Toxicity-related outcomes vary widely between cohorts, the most common being visual impairment, endocrinopathy, and neurocognitive disorders. Endocrinopathies, specially panhypopituitarism, are of major concern because they can potentially impair patient quality of life. Bishop et al reported no statistical differences between PBT and photon radiotherapy.[60]

Even though radiotherapy can help control disease progression, PBT has not been demonstrated to be superior to photon radiotherapy regarding toxicity in patients with craniopharyngioma. Further studies or strategies to approach this issue are still needed and expected to be addressed in the future.[61]

Ommaya reservoir in single cyst or dominant cystic lesions

Cysts are a morphological hallmark in almost all craniopharyngiomas with some lesions presenting with dominant cystic lesions and almost no solid components. This dominance in cystic components produces symptoms by direct compression of surrounding structures or by resultant hydrocephalus. There is a well-established tendency in neuroendoscopic procedures with the placement of an Ommaya reservoir allowing routine cyst aspiration and delivery of intracystic therapy.[58]  Placement of an Ommaya reservoir is a more conservative procedure and can be considered to postpone radiation therapy in younger patients or provide symptomatic relief if fluid reaccumulates during radiotherapy. 

Chen et al published their results with this therapeutic approach, which achieved rapid improvement of symptoms and optimal decompression of the cystic component of the lesion. Long-term control of the tumor was achieved in 67% of patients.[58] Similarly, Lohkamp et al found less endocrinologic complications in patients with cyst decompression versus patients undergoing surgical resection. [62]  Radiation therapy with hypofractionated radiation can follow cyst decompression, looking to minimize radiation exposure in adjacent structures. Proton therapy can be used after decompression of cystic structures, showing no differences in progression of the disease when compared with photon therapy. Lesser exposure to surrounding healthy tissue may help to reduce cognitive impairments after radiation therapy.[63, 64]

Surgical approaches

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.[49]  For select patients with suprasellar craniopharyngiomas, an extended endonasal endoscopic approach could provide a viable alternative to transcranial approaches.[65, 66, 67]

As mentioned, the preservation of function and quality of life in patients should be prioritized over total resection. Therefore, the best course of action is subtotal resection or cyst decompression followed by radiotherapy. The endoscopic endonasal route allows good visualization of the structures with a less invasive and aggressive approach. In pediatric patients, a shorter and narrower nasal corridor in contrast to their adult counterparts may make a trasnssphenoidal approach challenging. However, the latest evidence shows that this approach is feasible for the treatment of AC and PC in adults and children, even in more complex and bigger lesions such as tumors invading the hypothalamus and third ventricle, which are common indications for choosing a transcranial approach over an endoscopic one. [68]  An endoscopic endonasal approach is associated with better visibility, lower rates of diabetes insipidus and hypopituitarism, and lower rates of recurrence. A higher rate of CSF leak in patients undergoing an endoscopic endonasal approach can be a concerning issue. However, the ability to reach complex lesions with lower rates of comorbidities might justify it. An adequate reconstruction of the surgical site can improve CSF leak rates. An endoscopic endonasal approach can be considered a first-line approach for the treatment of craniopharyngiomas.[69]

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)[3, 4, 5, 6, 7] and (2) bleomycin for local intracystic chemotherapy.[8, 9, 10]

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.

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.[70]

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). Cystic lesions are the main target of this therapy, as brachytherapy showed no activity in solid portions of the tumor. 

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. A 2022 meta-analysis outlined positive outcomes in the treatment of craniopharyngiomas, especially monocystic or multicystic lesions. It reported optimal tumor growth rates and low comorbidities resulting from a single application of brachytherapy.[71]  However, brachytherapy is not routinely used and has been abandonded for the treatment of pediatric lesions due to multiple setbacks in dose calculations and outcomes.[58]

Intracystic chemotherapy

Intracystic injection of bleomycin[72]  and internal irradiation with radioisotopes have been reported to control the tumor cysts, yet numerous side effects have been described.[73]

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.[74] 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.[75]

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.[76] The efficacy of alpha interferon against squamous cell carcinoma of the skin, in which it induces apoptosis, is well established.[77] Jakacki et al.[78]  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.

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).[28, 79]

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[66]  (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[66] (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.[22, 23]  Imaging follow-up every 4-6 weeks and close clinical monitoring are indicated with sex hormone and/or growth hormone replacement.[80]

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.

Other Surgical Considerations

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

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),[3, 4, 5, 6, 7]  (2) bleomycin for local intracystic chemotherapy,[8, 9, 10]  and (3) possible new targeted treatments that arise from the vast ongoing molecular research

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.

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.

Author

Omar R Ortega-Ruiz, MD, Research at Deparment of Neurosurgery, Hospital Zambrano Hellion, San Pedro Garza García, Nuevo León, México

Disclosure: Nothing to disclose.

Coauthor(s)

George I Jallo, MD, Professor of Neurosurgery, Pediatrics, and Oncology, Director, Clinical Pediatric Neurosurgery, Department of Neurosurgery, Johns Hopkins University School of Medicine

Disclosure: Nothing to disclose.

Meleine M Martinez-Sosa, MD, Resident Physician, Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine

Disclosure: Nothing to disclose.

Nir Shimony, MD, Assistant Professor of Neurological Surgery, Division of Pediatric Neurosurgery, Department of Surgery, St Jude Children’s Research Hospital, Le Bonheur Neuroscience Institute, Le Bonheur Children’s Hospital, Baptist Children’s Hospital, and Semmes Murphey Clinic, University of Tennessee Health Science Center College of Medicine; Adjunct Faculty, Department of Neurosurgery, Johns Hopkins University School of Medicine

Disclosure: Nothing to disclose.

Chief Editor

Stephen L Nelson, Jr, MD, PhD, FAACPDM, FAAN, FAAP, FANA, Professor of Pediatrics, Neurology, Neurosurgery, and Psychiatry, Medical Director, Tulane Center for Autism and Related Disorders, Tulane University School of Medicine; Pediatric Neurologist and Epileptologist, Ochsner Hospital for Children; Professor of Neurology, Louisiana State University School of Medicine

Disclosure: Nothing to disclose.

Additional Contributors

Franco DeMonte, MD, FRCSC, FACS, Professor of Neurosurgery, Mary Beth Pawelek Chair in Neurosurgery, The University of Texas MD Anderson Cancer Center

Disclosure: Nothing to disclose.

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

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, The University of Texas MD Anderson Cancer Center

Disclosure: Nothing to disclose.

Lee S Hwang, University of Texas Southwestern Medical School

Disclosure: Nothing to disclose.

Morris D Groves, MD, JD, Associate Professor, Department of Neuro-Oncology, Division of Cancer Medicine, Associate Clinic Director for the Brain and Spine Center, The University of Texas MD Anderson Cancer Center

Disclosure: Received grant/research funds from Genentech for other; Received honoraria from Genentech for consulting; Received grant/research funds from GlaxoSmithKline for other; Received grant/research funds from AngioChem for other; Received grant/research funds from Pfizer/Celldex Therapeautics for other.

Acknowledgements

Jorge Kattah, MD Head, Program Director, Professor, Department of Neurology, University of Illinois College of Medicine at Peoria

Jorge Kattah, MD is a member of the following medical societies: American Academy of Neurology, American Neurological Association, and New York Academy of Sciences

Disclosure: Biogen Honoraria Consulting; Bayer Corporation Honoraria Consulting

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

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Reference Salary Employment

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The adamantinomatous craniopharyngioma is a histologically complex epithelial lesion with several very distinctive morphologic features (hematoxylin-eosin, x40).

T1-weighted MRI with gadolinium in sagittal (A) and coronal (B) views demonstrates the cystic nature of a craniopharyngioma. The calcified component is evident on axial CT imaging (C).

T1-weighted MRI with gadolinium reveals a large cystic craniopharyngioma in sagittal (A), axial (B), and coronal (C) views. There is associated elevation of the optic apparatus and displacement of the pituitary stalk.

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

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

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).

Coronal views of T1-weighted MRI for a patient with craniopharyngioma before gross total resection (A) and at postoperative follow-up evaluation (B). There was no sign of tumor recurrence, and the patient was neurologically and endocrinologically intact.

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

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

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).

T1-weighted MRI with gadolinium in sagittal (A) and coronal (B) views demonstrates the cystic nature of a craniopharyngioma. The calcified component is evident on axial CT imaging (C).

T1-weighted MRI with gadolinium reveals a large cystic craniopharyngioma in sagittal (A), axial (B), and coronal (C) views. There is associated elevation of the optic apparatus and displacement of the pituitary stalk.

Coronal views of T1-weighted MRI for a patient with craniopharyngioma before gross total resection (A) and at postoperative follow-up evaluation (B). There was no sign of tumor recurrence, and the patient was neurologically and endocrinologically intact.