Craniopharyngioma

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2]

Craniopharyngioma is a rare, benign tumor of the central nervous system. It is a partly cystic embryonic malformation that can occur in the sellar/parasellar region and can result in a wide array of symptoms such as headaches, nausea and vomiting, visual disturbances, and endocrine disturbances.It has an incidence of 0.5 to 2 cases per million persons per year. Half of these cases occur during the first two decades of life. It represents 1.2% to 4% of all childhood intracranial tumors. It has a classical bimodal distribution of incidence with increased incidence rates in patients aged five to 14 years and 50 to 74 years. Craniopharyngioma has a very high recurrence rate, with reported rates as high as 50%. There are two subtypes of craniopharyngioma: adamantinomatous and papillary. It most commonly presents with signs of increased intracranial pressure (ICP) including headache and nausea and vomiting along with visual and endocrine disturbances. In children, failure to thrive and decreased growth rate may be the initial presentation. Multiple modalities can be implemented in the management of craniopharyngioma, including neurological surgery, radiotherapy, and instillation of sclerosing substances.

Primitive concepts of the function of the pituitary gland were formulated in the 4th century BC by Hippocrates. Harvey Cushing (1869–1939), had a major impact in the understanding of pituitary function and surgery however he was not the first surgeon to attempt pituitary surgery; this honor went in 1889 to Sir Victor Horsley. Hermann Schloffer (1868–1937), an Austrian surgeon, guided by the works of Davide Giordano, performed the first transfacial transsphenoidal approach in 1907. In the 1960s, transphenoidal surgery underwent a revival and has been universally accepted to owing to the contributions of Guiot and Hardy.

Craniopharyngiomas occur in two histological subtypes; an adamantinomatous form and Papillary. Adamantinomatous form is the most common pediatric variant and the papillary form is found almost exclusively in adults.The pediatric form is thought to arise from epithelial remnants of the craniophayngeal duct or Rathke’s pouch, an embryologic structure that develops into the anterior pituitary. Both forms typically have solid and cystic components and are often calcified on imaging. Recent genetic analysis has also shown differences between these two subtypes. Mutations in B-catenin , a downstream effector of the Wnt pathway that is involved in cellular growth and development, has been described in 60–96% of adamantinomatous craniopharyngiomas. Papillary craniopharyngiomas recently have been discovered to frequently harbor V600E mutations of the BRAF gene, which is a key player in the mitogen-activated protein kinase pathway.

Craniopharyngiomas are epithelial tumors that usually arise in the pituitary stalk adjacent to the optic chiasm. On gross pathology, craniopharyngiomas are cystic or partially cystic with solid areas.The cyst is filled with a turbid, proteinaceous material of brownish-yellow color that glitters and sparkles because of a high content of floating cholesterol crystals On microscopic histopathology, it is categorized into two subtypes: adamantinomatous and papillary.

Craniopharyngioma must be differentiated from other pituitary masses such as sarcoid, pituitary adenoma, aneurysm, teratoma, tuberculosis, rathke cleft cyst, chordoma, hypothalamic glioma, hamartoma of tuber cinereum, histiocytosis, meningioma and optic nerve glioma.

The demographic patterns of craniopharyngioma are not well described because the tumor is rare. In addition, most cancer registries collect data only on malignant conditions and, therefore, they are not useful in the study of craniopharyngioma as it is considered to be a borderline histological malignancy. Incidence rates are similar in males and females and between caucasians and african americans. Tumors are more common among children of age 5 to 15 years and older adults of greater than 65 years while the lowest rates occur among those aged 15 to 34 years. Survival is highest for patients diagnosed at a younger age.

No predisposing risk factors have been identified.

Common complications of craniopharyngioma are long-term hormonal problems, visual defects and nervous system deficits. The prognosis of craniopharyngioma is good with treatment. The 5-year and 10-year survival rates are higher than 90%.

Brain MRI with and without contrast is the diagnostic study of choice. Computed tomography (CT) scan is optional and may show some calcifications that can be seen in these tumors. Imaging studies such as MR Angiography (MRA) or CT Angiogram (CTA) is decided on a case-by-case basis typically for surgical planning or if a possible vascular malformation is suspected.

Craniopharyngiomas are slow growing, and symptoms often are present for a year or more before the diagnosis is established. A wide range of symptoms may be present, depending upon the precise location of the tumor and its relationship to adjacent normal structures. Most common symptoms of craniopharyngioma include headache, nausea, vomiting, ataxia, polyuria, polydipsia, stunted growth, decreased libido, amenorrhea, weight gain, myxedema, vision loss, behavioral and learning problems.

The diagnosis of craniopharyngioma is often made late after the initial appearance of symptoms. Clinical picture at time of diagnosis often dominated by nonspecific manifestations of intracranial pressure like headache, nausea and vomiting. Primary manifestations are visual impairment and endocrine deficits.

Patients with craniopharyngioma may have abnormal pituitary hormone levels, which is suggestive of disruption of hormone production due to pressure effects on the pituitary gland. The hypothalamic-pituitary axis hormones, namely growth hormone, thyroid hormone, luteinising and follicle stimulating hormone should be measured together with cortisol levels and an assessment of serum and urine osmolality. In addition, an estimate of bone age and, for young females, ovarian ultrasonography is useful. Ideally, any abnormalities should be corrected pre-operatively but, at the very least, low cortisol levels and diabetes insipidus should be treated prior to a surgical procedure.

The CT findings depend on the subtype of craniopharyngioma. On CT, the adamantinomatous type is characterized by large cysts, vivid enhancement and peripheral calcifications. Papillary type tend to be more spherical in outline and usually lack the prominent cystic component; most are solid. Calcification is rare.

The diagnostic evaluation of craniopharyngioma includes high-definition brain imaging. Brain MRI with and without contrast is the gold standard. Computed tomography (CT) scan is optional and may show some calcifications that can be seen in these tumors. However CT is not specific enough as a stand alone diagnostic test. vascular imaging studies such as MR angiography (MRA) or CTA, is decided on a case-by-case basis typically for surgical planning or if a possible vascular malformation is suspected.

The predominant therapy for craniopharyngioma is surgical resection. Medical therapy, adjunctive chemotherapy and radiation may be required.

The predominant therapy for craniopharyngioma is surgical resection. Adjunctive chemotherapy and radiation may be required. Subcutaneous pegylated interferon alpha-2B has been used to treat cystic recurrences. It can also be treated with intracavitary instillation of radioactive P-32, bleomycin or interferon-alpha via stereotactic delivery or placement of an Ommaya catheter. Paclitaxel and carboplatin have shown to prevent recurrence of malignant craniopharyngiomas. 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. Reports of intracystic bleomycin use are limited. Other agents like interferon alpha are being tested in recent days.

Surgery is the mainstay of treatment for craniopharyngioma. Radical surgery is done either by transsphenoidal approach or by craniotomy. Recent studies propose subtotal resection with postoperative radiotherapy as the management of choice for craniopharyngiomas, especially in the pediatric population. More advanced radiotherapy modalities currently under investigation include Gamma Knife and cyberknife radiosurgery.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2]

Function of the pituitary gland were formulated in the 4th century BC by Hippocrates. Harvey Cushing (1869–1939), has had a major impact in the understanding of pituitary function and surgery but he was not the first surgeon to attempt pituitary surgery; this honor goes in 1889 to Sir Victor Horsley. Hermann Schloffer (1868–1937), an Austrian surgeon, performed the first transfacial transsphenoidal approach in 1907. In the 1960s, transsphenoidal surgery underwent a revival and has been universally accepted.

• Primitive concepts of the function of the pituitary gland were formulated in the 4th century BC by Hippocrates of Cos (460–370 BC).^[1]
• Joseph Lieutaud (1703–1780), a French physician and anatomist, named the pituitary stalk by proposing the term “Tige Pituitaire” .
• In 1886, Pierre Marie (1853–1940), a French physician, demonstrated the association between acromegaly and pituitary tumors.
• In 1840, von Mohr described the rapid development of obesity in a case of a pituitary tumor.
• Zenker in 1857 was the first to identify masses of cells resembling squamous epithelium along the pars tuberalis and pars distalis of the pituitary.^[2]
• In 1932, squamous epithelial cells were detected in the pituitary glands of childhood populations.^[2]
• in 1932 the name “craniopharyngioma” was introduced by Cushing.^[2]
• The first pituitary surgery was performed by Horsley in 1889 using a transfrontal approach.^[3]

• Transcranial approaches to the pituitary gland in the late 1800s and early 1900s resulted in high mortality rate.^[4]
• Schloffer suggested the use of a transsphenoidal route as a safer, alternative approach to the sella turcica.
• First successful removal of a pituitary tumor via the transsphenoidal approach in 1906.
• A. E. Halstead’s described in 1910 the sublabial gingival incision for the initial stage of exposure.^[5]
• Norman Dott, in 1923, continued to use the transsphenoidal procedure while others pursued transcranial approaches.
• Jules Hardy, who used intraoperative fluoroscopy in transsphenoidal approach to reach pituitary.^[4][5]

• The first endosopic surgery was performed by Hirschman, an otolaryngologist, in 1901.^[1]
• In 1957, Basil Hirschowitz, an American gastroenterologist, demonstrated the use of a fiberoptic endoscope.^[3]
• In 1965, Karl Storz revolutionized the use of fiberoptics by using an external cold light source coupled with the rod lens optical system.
• In pituitary transsphenoidal surgery, Guiot was the first, in 1961, to use the endoscope. ^[1]
• The endoscope was used in conjunction with transsphenoidal microsurgery, notably by Apuzzo, Bushe and Halves in the late 1970s.
• Endoscopic transsphenoidal procedure was introduced in the early 1990s.
• In 1992, Jankowski was the first to report the use of the pure endonasal endoscopic procedure for pituitary adenomas.^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2]

There are two subtypes of craniopharyngioma based on the histological and imaging features: adamantinomatous and papillary.

• Craniopharyngiomas are believed to be derive from Rathke cleft rather than squamous cell rests. ^[1]

• Craniopharyngiomas are classified according to their histologic appearance.
• The histological appearances of the two pathological subtypes are different, accounting for the different imaging features.
• The subtypes are said to differ not only in appearances, but also in prognosis and epidemiology.^[2]

• Adamantinomatous

• • This type is seen predominantly in children.^[1]
  • It consists of reticular epithelial cells which have appearances reminiscent of the enamel pulp of developing teeth.
  • There may be single or multiple cysts filled with thick oily fluid high in protein, blood products, and/or cholesterol, creating the so called “machinery oil”.^[3]
  • “Wet keratin nodules” are a characteristic histological feature.^[4]
  • Calcification is usually present in 90% of the cases.
  • They are more locally aggressive.
  • It has higher rate of recurrence.
  • Activating beta-catenin gene mutations are found in adamantinomatous tumors.^[5]

• Papillary

• • The papillary subtype is seen almost exclusively in adults.^[1]
  • It is formed of masses of metaplastic squamous cells.^[4]

• • “Wet keratin” nodule is absent.^[6]
  • Cysts do form, but these are less of a feature, and the tumor is more solid.^[3]
  • Calcification is uncommon or even rare.^[4]
  • They are less locally aggressive.
  • It has lower rate of recurrence.
  • BRAF V600E mutations are observed in papillary craniopharyngiomas.
• Mixed
  • 15% of them share imaging features and prognosis similar to the adamantinomatous subtye.^[7]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2]

Craniopharyngiomas are epithelial tumors that usually arise in the pituitary stalk adjacent to the optic chiasm. On gross pathology, craniopharyngiomas are cystic or partially cystic with solid areas.The cyst is filled with a turbid, proteinaceous material of brownish-yellow color that glitters and sparkles because of a high content of floating cholesterol crystals. On microscopic histopathology, it is categorized into two subtypes: Adamantinomatous and papillary.

• Craniopharyngioma is a nonglial intracranial tumor derived from a malformation of embryonic tissue. ^[1]
• There are differing hypotheses on its embryonic origin.
• Pathogenesis of craniopharyngioma is not completely understood.
• Some authorities advocate that it originates from ectodermal remnants of Rathke’s pouch. ^[2]
• Few pathologists believe that it originates from residual embryonal epithelium of the anterior pituitary gland and of the anterior infundibulum.

• According to this theory, craniopharyniomas arise from neoplastic transformation of embryonic squamous cell nests of Rathke’s pouch with the stomodeum.^[3]
• Cell remnants of the craniopharyngeal duct are spread through the intrasellar and suprasellar region.
• The rotation of the adenohypophysis is caused by different rates of cellular multiplication.
• Different rates of cellular multiplication results in a spread of cells of the craniopharyngeal duct to the suprasellar region.
• The rare location at the cerebellopontine angle could fit with this hypothesis.

• Papillary craniopharyngiomas are the result of metaplasia of the adenohypophyseal cells in the anterior pituitary.
• This theory is supported by the presence of metaplastic nests in the gland.^[2]

• On macroscopic examination, craniopharyngiomas are cystic or partially cystic with solid areas.^[4]
• Craniopharyngiomas can arise anywhere along the craniopharyngeal canal.
• It occur most often in sellar or suprasellar region but can have anterior extension to the prechiasmatic cistern and subfrontal spaces.^[4]
• Posterior extension into the prepontine , third ventricle, posterior fossa, and foramen magnum; and laterally toward the subtemporal spaces.
• Rare locations of craniopharyngiomas are; the nasopharynx , paranasal area , sphenoid bone, ethmoid sinus, intrachiasmatic area, temporal lobe.
• Craniopharyngiomas are supplied with blood coming from the anterior cerebral circulation.^[5]
• Several inflammatory cytokines have been shown to be elevated in the craniopharyngioma cyst fluid compared with cerbrospinal fluid (CSF).^[6]
• Tumor adhesion is the result of local inflammation.

• The histologic pattern consists of nesting of squamous epithelium bordered by radially arranged cells.
• Tumor is frequently accompanied by calcium deposition and have a microscopic papillary architecture.^[3]
• Two distinct types are recognized:^[7][8]

1. Adamantinomatous craniopharyngioma
2. Papillary craniopharyngioma

• In the adamantinomatous type, calcifications are visible on neuroimaging and are helpful in diagnosis.
• The papillary type rarely calcifies. On light microscopy, the cysts are seen to be lined by stratified squamous epithelium.
• Keratin pearls may also be seen.
• The cysts are usually filled with a yellow, viscous fluid which is rich in cholesterol crystals.
• Islands of densely packed cells merge with loosely cohesive aggregates of squamous cells known as stellate reticulum.
• Nodules of “wet keratin” representing remnants of pale nuclei embedded within an eosinophilic keratinous mass may be found.
• Cystic cavities containing squamous debris are lined by flattened epithelium.
• Granulomatous inflammation associated with cholesterol clefts and giant cells may be detectable, but this is more typical for xanthogranuloma.^[2]
• Piloid gliosis with abundant Rosenthal fibers is often seen at the infiltrative interface of the tumor and should not be mistaken for pilocytic astrocytoma.
• Malignant transformation of craniopharyngioma appears to be very rare.

• Multiple chromosomal abnormalities have been reported by classic cytogenetic analysis.
• Most tumors had abnormalities involving chromosomes 2 and 12.
• More than 70% of adamantinomatous craniopharyngiomas harbor a mutation of the β-catenin gene.
• Most of the mutations affect exon 3, which encodes the degradation targeting box of β-catenin.
• No mutations have been demonstrated in papillary craniopharyngioma.
• Comparative genomic hybridization studies on two large series of craniopharyngiomas have failed to show significant chromosomal imbalances.
• The mutations of genes encoding β-catenin (CTNNB1 and APC) are an exclusive characteristic of adamantinomatous craniopharyngioma.
• Few researchers demonstrated a causative effect of mutant β-catenin in the etiology of human adamantinomatous craniopharyngioma.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Fahimeh Shojaei, M.D.

On the basis of seizure, visual disturbance, and constitutional symptoms, craniopharyngioma must be differentiated from oligodendroglioma, meningioma, hemangioblastoma, pituitary adenoma, schwannoma, primary CNS lymphoma, medulloblastoma, ependymoma, astrocytoma, pinealoma, AV malformation, brain aneurysm, bacterial brain abscess, tuberculosis, toxoplasmosis, hydatid cyst, CNS cryptococcosis, CNS aspergillosis, and brain metastasis.

On the basis of seizure, visual disturbance, and constitutional symptoms, craniopharyngioma must be differentiated from oligodendroglioma, meningioma, hemangioblastoma, pituitary adenoma, schwannoma, primary CNS lymphoma, medulloblastoma, ependymoma, astrocytoma, pinealoma, AV malformation, brain aneurysm, bacterial brain abscess, tuberculosis, toxoplasmosis, hydatid cyst, CNS cryptococcosis, CNS aspergillosis, and brain metastasis.

ABBREVIATIONS

CNS=Central nervous system, AV=Arteriovenous, CSF=Cerebrospinal fluid, NF-2=Neurofibromatosis type 2, MEN-1=Multiple endocrine neoplasia, GFAP=Glial fibrillary acidic protein, HIV=Human immunodeficiency virus, BhCG=Human chorionic gonadotropin, ESR=Erythrocyte sedimentation rate, AFB=Acid fast bacilli, MRA=Magnetic resonance angiography, CTA=CT angiography

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2]

The demographic patterns of craniopharyngioma are not well described because the tumor is rare. In addition, most cancer registries collect data only on malignant conditions and, therefore, they are not useful in the study of craniopharyngioma which is considered to be a borderline histological malignancy. Incidence rates are similar in males and females and between caucasians and African Americans. Tumors are more common among children of age 5 to 15 years and older adults of greater than 65 years, while the lowest rates occur among those aged 15 to 34 years. Survival is highest for patients diagnosed at a younger age.

• Craniopharyngiomas constitute approximately 3% of all intracranial neoplasms.^[1]
• In children, craniopharyngiomas account for 5% of all tumours and 50% of all sellar and parasellar tumours.^[1]
• They are the most common pediatric brain tumor of nonglial origin, yet nearly half of all cases of craniopharyngiomas occur in adults.^[1]
• They appear to be more common, with higher incidence rates reported in Japan and some parts of Africa.
• They are approximately equally common in males and females.^[1]

• The overall incidence of craniopharyngioma is approximately 0.5 to 2 per 100,000 per year.^[1]
• The age distribution is bimodal with a peak in childhood and a second peak among middle-aged and older adults.^[1]
• No definite genetic relationship has been found and few familial cases reported. ^[1]

• A bimodal distribution by age was noted with peak incidence rates in children (aged 5-14 years; more common) and among older adults.^[2]

• There appears to be a similar incidence in both males and females.^[3]

• No racial predilection is seen in craniopharyngioma cases.
• Few studies show that there is a higher incidence rates reported in Japan and some parts of Africa. ^[1]

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2]

No predisposing risk factors have been identified.

No predisposing risk factors have been identified.

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1];Associate Editor(s)-in-Chief: Marjan Khan M.B.B.S.[2]

There are no screening methods recommended for craniopharyngioma.

There are no screening methods recommended for craniopharyngioma.

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