Craniopharyngioma

Craniopharyngiomas are rare squamous epithelial tumors with a solid and/or cystic structure that arise from the remnants of Rathke’s pouch along the pituitary stalk, in the suprasellar region. Craniopharyngiomas are histologically benign but tend to invade surrounding structures; thus, they should be treated as low-grade malignancies. Histologically, there are 2 types of tumors: adamantinomatous, which is more common in children; and papillary, which tends to occur in adults. Both these types can present with various symptoms depending on their location and extension patterns. The symptoms include headaches, nausea, vomiting, visual disturbances, endocrine dysfunction, and behavioral issues. Diagnosis is made by imaging and histology. Management typically involves surgical excision and radiation therapy.

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Overview

Definition

Craniopharyngiomas are rare squamous epithelial tumors with a solid and/or cystic structure, which arise from the remnants of Rathke’s pouch along the pituitary stalk, in line from the nasopharynx to the diencephalon (in the suprasellar region).

Craniopharyngiomas have benign histology but malignant behavior, meaning that they tend to invade the surrounding structures and are associated with a short life span. Therefore, despite their benign appearance on histology, they are considered low-grade malignancies.

Classification of nervous system tumors

Table: Classification of nervous system tumors
CategoriesSpecific tumors
Neuroepithelial tumors in the CNS
  • Astrocytomas, including glioblastoma multiforme
  • Oligodendroglioma
  • Ependymoma and choroid plexus tumors
  • Medulloblastomas (embryonal tumors)
Meningeal tumors
  • Meningiomas
  • Hemangioblastomas
Sellar region tumors
  • Craniopharyngioma
  • Pituitary adenoma
  • Pinealoma/pinealoblastoma
Primary CNS lymphomaPrimary CNS lymphoma
Metastasis to the brain (5x more common than primary brain tumors)Most commonly arising from:
  • Lung, breast, and renal cell carcinomas
  • Melanoma
Peripheral tumors
  • Schwannomas, including acoustic neuroma
  • Neuroblastoma

Epidemiology

  • Incidence: rare
    • Approximately 2 cases per 1,000,000 person years
    • Constitute 1%–3% of all primary brain tumors
  • Race/ethnicity: more common in patients of Japanese and African descent
  • Gender: equally common in men and women 
  • Age and subtype: A bimodal age distribution is observed.
    • Children: 
      • Peak diagnosis at 5–14 years of age
      • More commonly adamantinomatous subtype
    • Adults:
      • Peak diagnosis at 50–75 years of age
      • More commonly the papillary subtype
  • High recurrence rate (50%)
  • High morbidity rate

Classification

There are 2 primary types of craniopharyngiomas:

  • Adamantinomatous type:
    • Arises from the embryonic cells of the craniopharyngeal duct
    • Solid or cystic structures filled with a dark-brown or black fluid
    • Frequently progresses to calcification
  • Papillary type:
    • Arises from the cells of the anterior portion of the pituitary gland
    • Well circumscribed, solid or cystic, and filled with a viscous yellow fluid
    • Rarely calcify

Etiology and Pathophysiology

Craniopharyngiomas are squamous epithelial tumors that arise along the pituitary stalk in the suprasellar region, adjacent to the optic chiasm.

Etiology

Two main hypotheses have been proposed to explain the etiology of craniopharyngiomas:

  • Embryogenetic theory: 
    • Postulates that embryonic cells from the Rathke’s cleft and the remnants of the craniopharyngeal duct are the site of origin
    • The more likely etiology in the adamantinomatous type, which is more common in children
  • Metaplastic theory: 
    • Postulates that residual, mature squamous cells of the anterior hypophysis undergo metaplasia
    • The more likely etiology in the papillary type, which is more common in adults

Genetic mutations

  • Adamantinomatous type: CTNNB1 gene mutations → mutations in β-catenin protein 
    • A transcription factor in the Wnt signaling pathway 
    • Involved in patterning decisions during embryonic development, cell proliferation, and cell adhesion
  • Papillary type: activating mutations in the BRAF V600E oncogene  inhibition of apoptosis/enhanced cell survival

Tumor growth and extension

  • Arise in the pituitary stalk in the suprasellar region
  • Project into the hypothalamus
  • May extend horizontally along the path of least resistance, which may be anteriorly, posteriorly, and/or laterally:
    • Anterior extension:
      • Prechiasmatic cistern
      • Subfrontal spaces
    • Posterior extension:
      • Prepontine cistern
      • Interpeduncular cistern
      • Cerebellopontine angle
      • 3rd ventricle
      • Posterior fossa
      • Foramen magnum
    • Lateral extension: toward the subtemporal spaces
  • Clinical presentation will depend on the affected areas of the brain. Commonly affected areas include:
    • Anterior pituitary (and its hormones)
    • Optic chiasm and/or optic nerves
    • Hydrocephalus (secondary to compression of the 3rd ventricle)

Clinical Presentation

Craniopharyngiomas are slow-growing tumors; therefore, there is an insidious development of symptoms usually after the tumor attains a diameter > 3 cm. The onset of symptoms is usually 1‒2 years after the tumor develops.

General symptoms

  • Headache: 
    • Most common presentation, seen in 50%‒80% of cases
    • Presentation is progressive, dull, continuous, and positional.
  • Lethargy 
  • Nausea and/or vomiting

Visual disturbances

Visual disturbances are seen in about 40%‒65% of patients and include: 

  • Bitemporal hemianopia
  • Diplopia
  • Decrease in visual acuity 
  • Constriction of visual field

Endocrine dysfunction

Some type of endocrine dysfunction is common in craniopharyngiomas, and is seen in about 65%‒90% of patients. Deficiencies in growth hormone (GH), gonadotropins, thyroid-stimulating hormone (TSH), and adrenocorticotropic hormone (ACTH) can all be seen.

  • GH deficiencies:
    • In young patients: growth failure and delayed puberty 
    • In adults: obesity, fatigue
  • Hypothyroidism (↓ TSH, approximately 40% of patients):
    • Weight gain/obesity
    • Cold intolerance
    • Constipation 
    • Fatigue 
    • Amenorrhea in women
    • Impotence in men
  • Adrenal dysfunction (↓ ACTH, approximately 25% of patients):
    • Orthostatic hypotension
    • Hypoglycemia 
    • Hyperkalemia 
    • Fatigue
    • Cardiac arrhythmias 
  • Diabetes insipidus (↓ antidiuretic hormone, approximately 20% of patients):
    • Polydipsia
    • Polyuria

Cognitive dysfunction and behavioral issues

Cognitive dysfunction and behavioral issues may be due to impacts on the thalamus, hypothalamus, and frontal lobes.

  • Hyperphagia 
  • Anorexia
  • Psychomotor retardation
  • Emotional immaturity
  • Apathy 
  • Short-term memory deficits
  • Incontinence 

Signs of increased intracranial pressure (ICP)

Increased intracranial pressure may occur due to obstructive hydrocephalus, and the signs/symptoms may include:

  • Papilledema
  • Diplopia
  • Nausea/vomiting
  • Headache

Diagnosis

Diagnosis of craniopharyngiomas should be a multidisciplinary process, including the involvement of specialists in endocrinology, neuro-ophthalmology, and neurosurgery.

Imaging

The main approach to the diagnosis of craniopharyngiomas is by using radiological imaging, specifically MRI and CT, which reveal a sellar/suprasellar calcified cyst. The tumors may have both solid and cystic components.

  • MRI with and without contrast:
    • Considered the gold standard
    • Provides better information on the tumor location and its association with the surrounding structures
    • Tumors enhance with contrast.
    • Extension:
      • Cystic components typically extend anteriorly and/or laterally, and may wrap around solid components.
      • Solid components typically extend posteriorly and/or laterally.
    • T1-weighted images: 
      • Cysts can have a variable appearance depending on the protein, blood, and/or cholesterol content.
      • Solid components appear isointense.
    • T2-weighted images: 
      • Cysts are hyperintense.
      • Solid portions are heterogenous and isointense to hypointense.
  • CT:
    • The best test to detect calcifications, as they are seen vividly on CT
    • Tumors enhance with contrast.
    • Cysts present as hypointense lesions (resemble the fluid density of CSF).
    • Solid portions are isointense.
MRI imaging of craniopharyngioma

Magnetic resonance imaging of craniopharyngioma

Image by Roy Strowd, MD. License: CC BY-NC-SA 4.0

Histology

  • Adamantinomatous type:
    • Reticular epithelial masses are observed.
    • Compactly arranged squamous cells
    • Palisading basal layer of small cells
    • A stellate reticular zone enclosed by the basal layer of cells
    • “Wet keratin”: nodules of keratin that appear plump (aggregated wet keratin is what calcifies)
  • Papillary type:
    • Islands of squamous metaplasia and fibrovascular tissue seen in connective tissue stroma
    • No keratin nodules

Additional workup

The following should be completed if not done at initial presentation:

  • Full neuro exam
  • Ophthalmology assessment
  • Endocrine workup:
    • TSH levels
    • GH levels
    • Gonadotropin levels: follicle stimulating hormone (FSH) and luteinizing hormone (LH)
    • Prolactin
    • Morning and evening cortisol levels
    • Serum electrolytes
    • Serum and urine osmolality

Management and Prognosis

Primary management options

Surgery is indicated in almost all cases, but there are 2 primary management options:

  • Aggressive approach: total surgical resection
    • Total resection is the preferred treatment approach.
    • Total surgical resection is dependent on the location and size of the tumor.
    • Considered with caution in children due to a high association with hypothalamic injury and deficits with gross total resection
  • Conservative approach: subtotal resection + radiotherapy 
    • Considered more often to ensure a good quality of life postoperatively
    • Indications:
      • Residual tumor after surgery
      • Recurrence of the tumor
    • Radiation therapy options:
      • Stereotactic radiosurgery
      • Intensity-modulated radiation therapy
      • Proton beam radiation therapy

Cyst management

While surgical management is typically required, there are additional options available to reduce cysts, including:

  • Percutaneous aspiration (especially if the cyst is impinging on the optic anatomy)
  • Intracavitary irradiation
  • Intracavitary chemotherapy (can leak from a cyst and cause severe neurotoxicity)

Complications

  • Craniopharyngiomas can cause several complications:
    • Endocrine
    • Neurologic
    • Visual
    • Vascular
  • Patients should be managed by multidisciplinary teams to address issues specific to each patient.

Prognosis

  • The prognosis of craniopharyngiomas depends on the recurrence of the tumor. 
  • Frequent recurrence is usually associated with a poor prognosis.
  • Survival rates:
    • Approximately 90% survival rate at 2 years
    • Approximately 85% survival rate at 5 years 
  • 5-year survival based on age:
    • 93% in patients 1‒14 years of age
    • 88% in adolescents and young adults
    • 78% in patients > 40 years of age

Differential Diagnosis

The conditions listed below should be considered in the differential diagnosis for craniopharyngiomas. Most cases will present similarly and can be differentiated based on differences in imaging and histology.

  • Pituitary adenomas: benign tumors within the pituitary gland, many of which are hormonally active. The most common type is a prolactinoma, although they may secrete any of the hormones produced by the pituitary gland. The clinical presentation may include headache, fatigue, bitemporal hemianopia and/or diplopia, and findings associated with elevated hormone levels. Like craniopharyngioma, pituitary adenomas are located within the sella, but only rarely contain cysts or calcifications.
  • Glioblastoma multiforme: a rapidly progressive WHO grade IV astrocytoma that arises from astrocytes (glial cells in the brain) and clinically presents as headache, nausea, drowsiness, blurred vision, personality changes, and seizures. Imaging, clinical presentation, and biopsy are the mainstays for diagnosis. Management includes radiotherapy, chemotherapy, and surgical excision. Prognosis is poor even with treatment. Unlike hemangioblastoma, glioblastoma multiforme is not associated with von Hippel-Lindau (VHL) disease.
  • Hemangioblastoma: a rare vascular tumor of the CNS, often associated with VHL disease, which usually affects the brain but can also involve the spinal cord or retina. Presenting symptoms include headache and neurological deficits based on the location of the tumor. While hemangioblastomas may have both solid and cystic components, they tend to be located in the cerebellum or spinal cord and do not generally calcify.
  • Meningioma: a tumor arising from the meninges of the brain and spinal cord. Meningiomas are commonly asymptomatic, but can present with headache, seizures, and visual disturbances. Meningiomas are diagnosed using MRI and a biopsy. Asymptomatic cases are typically observed while symptomatic patients are treated surgically or with radiation. Unlike craniopharyngiomas, meningiomas are always near the meninges and often have imaging findings of dural attachment (e.g., dural tail sign).

References

  1. Harsh, G.R., Recht, L.D., Marcus, K.J. (2020). Craniopharyngioma. In Eichler, A.F., (Ed.), UpToDate. Retrieved June 2, 2021, from https://www.uptodate.com/contents/craniopharyngioma
  2. Jallo, G.I. (2017). Craniopharyngioma. Medscape. Retrieved June 2, 2021, from https://emedicine.medscape.com/article/1157758-overview
  3. Johns Hopkins Medicine (2020). Craniopharyngioma. https://www.hopkinsmedicine.org/health/conditions-and-diseases/craniopharyngioma
  4. Mayo Clinic (2019). Brain tumor – Craniopharyngioma. https://www.mayoclinic.org/diseases-conditions/craniopharyngioma/cdc-20354175
  5. Lakis, N. (2021). Adamantinomatous craniopharyngioma. Pathology Outlines. Retrieved April 14, 2021, from https://www.pathologyoutlines.com/topic/cnstumoradamcraniopharyngioma.html
  6. Lakis, N. (2021). Papillary craniopharyngioma. Pathology Outlines. Retrieved April 14, 2021, from https://www.pathologyoutlines.com/topic/cnstumorpapcraniopharyngioma.html
  7. Kiliç, M., Can, S.M., Özdemir, B., Tanik, C. (2019). Management of craniopharyngioma. J Craniofac Surg. 30(2), e178–e183. https://pubmed.ncbi.nlm.nih.gov/30640850/
  8. Müller, H.L., et al. (2019). Craniopharyngioma. Nat Rev Dis Primers. 5(1), 75. https://pubmed.ncbi.nlm.nih.gov/31699993/
  9. Kassam, A.B., et al. (2008). Expanded endonasal approach, a fully endoscopic transnasal approach for the resection of midline suprasellar craniopharyngiomas: A new classification based on the infundibulum. J Neurosurg. 108(4), 715–728. https://pubmed.ncbi.nlm.nih.gov/18377251/

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