NORD gratefully acknowledges Etienne Leveille, MD Candidate, McGill University School of Medicine, and George I. Jallo, MD, Professor of Neurosurgery, Pediatrics, and Oncology, Director, Clinical Pediatric Neurosurgery, Department of Neurosurgery, Johns Hopkins University School of Medicine, for assistance in the preparation of this report.
A craniopharyngioma is a benign tumor (neoplasm) derived from embryonic tissue from the sellar region and its surroundings (parasellar region). The sellar region is located in the center of the cranial base and notably comprises the pituitary gland, the “master gland” of the body, and the sella turcica, a bony depression in the skull (in the sphenoid bone, specifically) where the pituitary gland sits.
Craniopharyngiomas develop in around 0.5 to 2 per million individuals each year and has a bimodal distribution, 5 to 14 years of age and 50 to 74 year. Many experts consider craniopharyngiomas to be a chronic disease, as they tend to recur even when they have been completely removed (resected) surgically. The tumor itself is usually not dangerous, as it is benign and only very rarely becomes malignant. However, the tumor’s location is such that it can compress the pituitary gland and lead to hormonal dysfunction. The optic chiasm, where the two optic nerves partially cross, is located above the pituitary gland and can therefore be compressed by a craniopharyngioma, leading to visual defects. The hypothalamus, to which the pituitary gland is connected, can also be damaged, especially after surgery. As the hypothalamus is a regulator of many biological functions, damage to this structure is associated with symptoms such as the development of obesity (hypothalamic obesity) and disruption of sleep cycles. Another anatomical structure that can be compressed by a craniopharyngioma is the foramen of Monro within the ventricles. If this foramen is occluded, the cerebrospinal fluid that normally circulates in the brain and spinal cord will accumulate (a condition known as hydrocephalus), potentially leading to numerous symptoms, including an enlarged head in babies. Headaches and nausea can also occur due to an elevation in intracranial pressure. Treatment of craniopharyngioma includes surgical resection of the tumor and radiation therapy, especially when the tumor is not entirely resectable due to its location. Specific hormonal treatment might also be required, depending on the needs of the patient.
There are two types of craniopharyngioma: adamantinomatous and papillary. The first type most commonly occurs in children, while the second is more common in adults. Adamantinomatous craniopharyngiomas arise from cells from an embryologic structure known as the craniopharyngeal duct. They can be solid or form a hollow (cystic) structure filled with dark brown to black (motor oil-like) fluid and are frequently calcified. Papillary craniopharyngiomas are rarer and arise from cells from the anterior part of the pituitary gland. They are usually well circumscribed and can also be solid or cystic, although they are filled with yellow and viscous fluid. They rarely calcify. The clinical manifestations of both types of craniopharyngioma are largely similar. As craniopharyngiomas are rare tumors with atypical and non-specific symptoms, they can be diagnosed years after the appearance of symptoms. An early diagnosis is beneficial, as it can greatly improve the quality of life of affected individuals and reduce the risk of long term complications.
They are almost always benign but they can cause symptoms by compressing closely located important anatomical structures such as the pituitary gland, the hypothalamus, and the crossing of the two optic nerves (optic chiasm). Limb weakness (paresis), difficulty walking, seizures, and psychiatric symptoms such as paranoid delusions can also occur from compression of the brain. Another general consequence of tumor compression is a raise in intracranial pressure, which can cause symptoms such as headache and nausea. As craniopharyngiomas are difficult to treat and located in an anatomical location difficult to access and close to many important structures, patients can experience many symptoms that are related to the treatment of the disease rather than the disease itself.
Pituitary gland dysfunction
The pituitary gland is the “master gland” of the body and its integrity is crucial to many hormonal processes throughout the body. Most patients with a craniopharyngioma experience hormonal (endocrine) deficits due to compression of the pituitary gland by the tumor. Deficits can affect every hormonal pathway influenced by the pituitary gland and tend to be more pronounced in patients with adult-onset craniopharyngiomas. GH (growth hormone) deficiency can lead to a decreased growth rate in children (for more information on this disorder, choose “growth hormone deficiency” as your search term in the Rare Disease Database). Delayed puberty and absence of menses in women (amenorrhea) can occur in cases of FSH and LH (gonadotropins) deficiency. Less commonly, craniopharyngiomas can also trigger precocious puberty (for more information on this disorder, choose “precocious puberty” as your search term in the Rare Disease Database). ACTH (adrenocorticotropic hormone) deficiency can cause many symptoms such as weakness and tiredness (for more information on this disorder, choose “ACTH deficiency” as your search term in the Rare Disease Database). TSH (thyroid stimulating hormone) deficiency is also associated with many clinical manifestations, including fatigue, generalized weakness, menstrual irregularity, and forgetfulness. Compression of the pituitary gland can also be the cause of a disorder, known as central diabetes insipidus (which is not related to the more common diabetes mellitus, also known as “sugar diabetes”), that is characterized by excessive thirst (polydipsia) and excessive urination (polyuria) (for more information on this disorder, choose “Insipidus” as your search term in the Rare Disease Database).
The hypothalamus is connected to the pituitary gland and controls its hormone secretion, in addition to being responsible for the regulation of numerous biological processes. Hypothalamic dysfunction can occur due to compression of the hypothalamus by the tumor, but can also occur as a consequence of surgical removal (resection) of the tumor. One major symptom related to dysfunction of the hypothalamus is hypothalamic obesity, a type of obesity that occurs even with caloric restriction and lifestyle changes. Froelich’s syndrome is a combination of hypothalamic obesity, delayed sexual development, and small testes that is caused by damage to the hypothalamus (for more information on this disorder, choose “Froelich’s syndrome” as your search term in the Rare Disease Database). Other symptoms of hypothalamic dysfunction include changes in behavior and imbalances in body temperature, thirst, heart rate and blood pressure. Hypothalamic dysfunction can also lead to a disorders of sleep cycle such as non-24-hour sleep-wake syndrome. Symptoms of this disorder include night-time insomnia and excessive daytime sleepiness (for more information on this disorder, choose “N24” as your search term in the Rare Disease Database).
Optic nerves and optic chiasm compression
The optic nerves, which carry visual information to the brain, partially cross right above the pituitary gland to form a structure called the optic chiasm. Both the optic nerves and the optic chiasm can be compressed by a craniopharyngioma. This can lead to two main visual symptoms: blurry vision (decreased visual acuity) and loss of vision in certain areas of the visual field (visual field defects). Visual symptoms are common in individuals with a craniopharyngioma.
Foramen of Monro occlusion
The brain contains the ventricular system: a system of four cavities (ventricles) where cerebrospinal fluid (CSF), is produced and circulates. A craniopharyngioma might occlude some of the channels that connect ventricles together (foramen of Monro). If the foramen of Monro are occluded, cerebrospinal fluid will not be able to circulate properly and will accumulate (hydrocephalus). Symptoms associated with hydrocephalus are numerous and depend on the age of the affected individual. Babies might feed poorly, be irritable, and have an enlarged head. Children and adults can have symptoms such as neck pain, headaches, vomiting, and blurred vision.
Treatment-associated (iatrogenic) complications
Craniopharyngiomas are difficult to remove surgically, as they are usually located near multiple anatomical structures that can be damaged during surgery. Craniopharyngiomas also tend to recur, even when they seem to have been removed completely. Many patients therefore have to undergo multiple surgeries during their lifetime. Consequences of surgery include damage to close anatomical structures, especially the pituitary gland and the hypothalamus. Cognition, memory, and attention deficits can also be consequences of surgery. Especially in patients where the tumor cannot be entirely removed, radiation therapy usually follows surgical treatment. The internal carotid arteries can be damaged by such therapy (radiation-induced vasculopathies), leading to cerebrovascular complications such as dilatation and weakening of blood vessel wall (aneurysm), and Moyamoya disease, where the internal carotid arteries are narrowed, which can lead to further complications such as headaches, strokes, and seizures (for more information on this disorder, choose “Moyamoya” as your search term in the Rare Disease Database). Exposure to radiation is also a risk factor for the development of brain tumors such as gliomas (for more information on this disorder, choose “glioma” as your search term in the Rare Disease Database).
Long term outcomes
When properly managed, individuals with a craniopharyngioma have an over 90% survival rate over 20 years. Many experts consider craniopharyngiomas to be a chronic disease, as tumor recurrence rates are high, even with apparent complete resection of the tumor. Significant complications that can lead to mortality include strokes, cardiac complications, respiratory complications, chronic hypothalamic insufficiency, hormonal deficiencies, and seizures. In very rare cases, craniopharyngiomas can become malignant (malignant transformation).
Craniopharyngiomas are caused by malformations of embryonic tissue in the sellar and parasellar regions. Adamantinomatous craniopharyngioma, which occur mostly in children, and papillary craniopharyngioma, which occur mostly in adults, have different embryological origins.
Adamantinomatous craniopharyngiomas arise from the transformation into tumor cells (neoplastic transformation) of cells from the craniopharyngeal duct, an embryological structure connected to Rathke’s pouch, which gives rise to part of the pituitary gland. The exact cause of development of adamantinomatous craniopharyngioma is unknown, although mutations in the CTNNB1 or APC genes are present in more than 70% of tumors. These genes produce a protein, known as beta-catenin, that is important in the development of the embryo (embryogenesis). Mutations in these genes might therefore play a role in the development of adamantinomatous craniopharyngiomas.
Papillary craniopharyngiomas are caused by a change in cell type (metaplasia) of cells in the anterior pituitary gland. This leads to the formation of nests made from a cell type known as squamous cells. As for adamantinomatous craniopharyngioma, the exact cause of development of papillary craniopharyngioma is unknown.
Craniopharyngiomas occur in around 0.5 to 2 people per million each year and represent around 1.2 to 4% of all intracranial tumors in children. They mostly develop in two age groups (bimodal incidence peaks): children aged 0 to 14 years and adults aged 50 to 74 years. They occur in men and women equally. Adamantinomatous craniopharyngioma are more common, representing 86 to 89% of all craniopharyngiomas.
A diagnosis of craniopharyngioma is based on three main modalities: clinical history and physical exam, laboratory testing, and imaging.
Clinical history and physical exam
A diagnosis of craniopharyngioma requires an extensive clinical history and physical examination. Clinical manifestations that rise a suspicion of craniopharyngioma include a combination of headache, visual impairment, decreased growth rate, increased thirst and urination (polydipsia and polyuria), and other signs of hormonal (endocrine) deficiency.
Laboratory testing will usually be needed to confirm clinical suspicion of endocrine deficiency. Typically tests for craniopharyngioma include evaluation of serum electrolytes, as well as all the hormones that can be affected by pituitary dysfunction: GH, IGF-1, TSH, free thyroxin, cortisol, FSH, LH, testosterone, estradiol, and prolactin.
Computed tomography (CT scan) and magnetic resonance imaging (MRI) are the imaging modalities of choice to diagnose craniopharyngiomas. CT scan is used to detect tumor calcification, while a MRI can be used to detect fluid accumulation inside cystic tumors.
Individuals with a craniopharyngioma might initially present with neurological, visual, and hormonal dysfunctions and might need to be evaluated by neurologists, ophthalmologists, and endocrinologists. A radiologist or neuro-radiologist will then be required to interpret medical imaging. The combination of clinical manifestations, laboratory values, and medical imaging will lead to a clinical diagnosis of craniopharyngioma. The diagnosis can be confirmed by a neuropathologist that will analyze the tumor microscopically once it has been removed (resected).
Neurosurgical treatment is central to the management of craniopharyngioma. If there is no risk to damage nearby anatomical structures, a neurosurgeon will remove (resect) the entirety of the tumor. If the tumor is in proximity to crucial structures, the surgical team might decide not to remove the entirety of the tumor. Radiation oncologists will then be involved to administer radiotherapy to patients. There is no clear consensus on the balance that should be adopted between attempt at resecting the tumor and radiation therapy. Multiple surgical procedures might be required throughout a patient’s lifetime, as craniopharyngiomas tend to recur even when they seem to have been completely resected.
Endocrinologists will often be involved, as hormone replacement therapy is required to treat patients with hypothalamic and pituitary gland dysfunction. Hypothalamic obesity is also an issue that can significantly impact the quality of life of affected individuals. Medication, such as Octreotide, that reduces insulin secretion, and bariatric surgery might be indicated for some patients suffering from morbid obesity. Due to the high rate of recurrence of craniopharyngioma and the numerous effects they can have on the body, affected individuals will usually have to be followed by numerous medical specialists throughout their life.
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