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Pediatric Craniopharyngioma
Introduction
Craniopharyngiomas are rare, benign tumors of the central nervous system (CNS) that typically arise in the suprasellar region and often extend to involve critical structures such as the hypothalamus, optic chiasm, cranial nerves, third ventricle, and major blood vessels. These tumors are classified into 2 distinct subtypes—adamantinomatous and papillary—each with unique genetic characteristics, imaging features, and age-related presentations. Clinically, craniopharyngiomas can cause a range of symptoms, including headaches, nausea, vomiting, and significant visual and endocrine disturbances.
Due to their proximity to vital neurovascular structures, craniopharyngiomas present a complex therapeutic challenge, requiring a multidisciplinary approach involving neurosurgeons, oncologists, neuroophthalmologists, neurologists, endocrinologists, and pediatricians. Surgical resection remains the primary treatment modality; however, achieving complete tumor removal without causing substantial morbidity is difficult. Even with successful intervention, patients often experience long-term complications such as panhypopituitarism, visual impairment, hypothalamic obesity, and neurocognitive dysfunction, significantly impacting their quality of life.[1][2][3][4] These challenges underscore the need for individualized treatment strategies that balance tumor control with functional preservation.
Etiology
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Etiology
There are 2 major theories regarding the development of craniopharyngiomas: the embryonic and metaplastic theories. These 2 theories correlate with the 2 histologic subtypes of craniopharyngiomas: adamantinomatous craniopharyngioma (ACP) and papillary craniopharyngioma (PCP).[5] The embryonic theory is related to the development of ACP, the more common subtype. During embryogenesis, there is an outpouching of the ectodermal roof of the stomodeum. This outpouching, known as Rathke pouch, extends cranially towards the floor of the diencephalon to later form the adenohypophysis or anterior pituitary gland. While migrating cranially, its extension forms the craniopharyngeal duct, which later involutes.
On some occasions, involution is incomplete, and remnants of ectodermal cells can remain. These embryonic cells can proliferate around the extension of the craniopharyngeal duct and develop into a craniopharyngioma. Somatic mutations in CTNNB1 are proposed to be responsible for ACP development.[6] CTNNB1 mutations are point mutations in exon 3 leading to excessive beta-catenin protein, thus activating the WNT signaling pathway, leading to cell proliferation, invasion, and tumor development.[7][8]
The metaplastic theory is related to the development of PCP. The adenohypophyseal cells of the pars tuberalis can undergo metaplasia, resulting in the formation of squamous cell nests, further proliferating and leading to PCP. Somatic mutations in BRAFV600E have been associated with PCP.[6] BRAF activates the mitogen-activated protein kinase pathways, usually upregulated in certain tumors.[6][9][10]
Epidemiology
Craniopharyngiomas have an incidence of 0.5 to 2 cases per million persons per year.[11][12][13] Craniopharyngiomas can be diagnosed at any age, although it is generally considered a pediatric disease, accounting for 1.2% to 4% of all intracranial tumors.[11][14] They are the most common nonneuroepithelial tumors in children.[12][15]
ACPs have a classical bimodal age distribution, with an increased incidence rate in 5 to 14 and 50 to 74 years of age, while PCPs are almost exclusively diagnosed in adults.[13][16][17] There is no statistical difference in the incidence based on gender, race, and geographical location. Rare instances of familial cases of craniopharyngioma have been reported.[18][19][20][21]
Pathophysiology
The sellar and suprasellar region is the most common location for craniopharyngiomas, with 95% exhibiting a suprasellar component. Tumor location directly influences its pathophysiology. Compression of normal pituitary tissue can lead to anterior pituitary deficiencies. At the same time, the involvement of the optic chiasm and optic nerves may cause visual disturbances ranging from blurry vision to complete blindness. When the third ventricle is affected, hydrocephalus can develop. Significant suprasellar extension may result in nonspecific symptoms of intracranial hypertension, such as headache, nausea, and vomiting. Cranial nerve palsies involving the oculomotor, abducens, and trochlear nerves can also occur due to tumor involvement in this region.
Histopathology
Craniopharyngiomas are histologically benign World Health Organization grade I tumors.[22] ACPs are most often solid and cystic tumors. The solid component is characterized by dense nodules and trabeculae of squamous epithelium bordered by a columnar epithelium palisade, sometimes called a "picket fence." These nests of squamous epithelium are surrounded by loose aggregates of squamous epithelium known as stellate reticulum. The cystic part has a yellow-brown, cholesterol-rich fluid. Nodules of “wet keratin” represent desquamated cells that form large, pale, eosinophilic masses that occasionally contain calcium. Piloid gliosis with abundant Rosenthal fibers is suggestive of invasion of surrounding brain tissue.
PCPs are characterized by well-differentiated squamous epithelium lacking surface maturation, with occasional goblet cells and ciliated epithelium. Calcifications are rare in papillary tumors. PCPs are well-circumscribed compared to ACPs, and invasion of surrounding brain tissue is much less common.[23]
History and Physical
Craniopharyngiomas are slow-growing tumors often diagnosed late once patients develop symptoms related to increased intracranial pressure, visual disturbances, or endocrinopathies. Headaches, nausea, and vomiting are common initial complaints, occurring in approximately 50% of patients, often due to elevated intracranial pressure or meningeal irritation from cystic fluid.[24] Visual symptoms are present in 62% to 84% of cases, with bitemporal hemianopsia being the most common due to optic chiasm compression.[25] Optic pathway dysfunction is found in 50% to 75% of patients, and because children may not recognize visual deficits early, permanent vision loss can occur. Severe cases may lead to optic nerve atrophy, papilledema, and significant visual field deficits.
Endocrine dysfunction is a hallmark of craniopharyngiomas, with approximately 80% to 90% of patients presenting with at least 1 hormonal deficiency. However, only 15% of children initially present with endocrinopathies, often delaying diagnosis. On initial presentation, most children will be found to have stunted growth, obesity, and delayed puberty.[26][27] Growth hormone deficiency is prevalent in 75% of pediatric cases, leading to short stature, a primary reason for pituitary evaluation. Gonadotropin deficiency affects 85% of children, resulting in delayed puberty—defined as the absence of breast development by age 12 in girls or lack of testicular growth by age 14 in boys. Thyroid-stimulating hormone deficiency is seen in 2% to 25% of pediatric cases, causing symptoms of hypothyroidism such as weight gain, fatigue, dry skin, and failure to thrive. Adrenocorticotropic hormone deficiency occurs in 25% to 70% of patients and may present subtly with weight loss, fatigue, dizziness, anorexia, and hypoglycemia. Vasopressin deficiency (diabetes insipidus) is reported in 9% to 38% of cases, leading to excessive thirst and urination.
Neurologic and cognitive impairments are also recognized manifestations. Behavioral and cognitive dysfunction, including visual and olfactory hallucinations, has been reported in children. Motor deficits such as monoplegia and hemiplegia, as well as seizures and unsteady gait, are seen in approximately 10% of cases. Cranial nerve involvement can result in oculomotor, abducens, and trochlear nerve palsies. The combination of these symptoms necessitates a high index of suspicion for early diagnosis and timely intervention to prevent permanent complications.
Evaluation
Multidisciplinary Approach
The evaluation of craniopharyngioma requires a multidisciplinary team involving neurosurgeons, oncologists, endocrinologists, and neuroophthalmologists to ensure comprehensive assessment and management.[27] A comprehensive, multidisciplinary approach ensures accurate diagnosis and guides optimal management strategies.
Imaging Studies
Craniopharyngioma is readily diagnosed using computed tomography (CT) and magnetic resonance imaging (MRI). MRI is the gold standard for diagnosing intracranial tumors, providing precise anatomical details of the tumor and its relationship with surrounding structures.
- ACP:
- CT scan
- This tumor appears as a mixed solid-cystic tumor with calcifications present in 90% of cases.[28]
- MRI
- Due to their high protein content, cystic components appear iso to hyperintense on T1-weighted imaging and are typically hyperintense on T2-weighted imaging. Solid components show mixed T2 signal intensities with avid contrast enhancement.
- CT scan
- PCP:
- CT scan
- This tumor typically appears as a solid mass with soft tissue densities and rare calcifications.
- MRI
- Solid tumors are iso to hypointense on T1-weighted imaging, with variable T2 signal intensity and avid contrast enhancement.[29]
- CT scan
Both imaging modalities are essential for identifying associated hydrocephalus, which may develop due to third ventricular obstruction.
Visual Examination
A complete neuroophthalmologic evaluation is crucial, as 62% to 84% of patients present with visual disturbances.[25]
- Acuity and visual field testing (perimetry)
- Identifies classic bitemporal hemianopsia due to optic chiasm compression
- Fundoscopy
- May reveal papilledema in patients with increased intracranial pressure due to hydrocephalus
Endocrine Evaluation
Given the tumor’s proximity to the hypothalamic-pituitary axis, comprehensive hormonal testing is necessary. Laboratory tests should include:
- Morning fasting cortisol and adrenocorticotropic hormone
- Evaluates adrenal insufficiency
- Thyroid-stimulating hormone and free T4
- Assesses for central hypothyroidism
- Gonadotropins (follicle-stimulating hormone [FSH], luteinizing hormone [LH]), estradiol (females), testosterone (males)
- Identifies hypogonadotropic hypogonadism
- Growth hormone and insulin-like growth factor-1
- Screens for growth hormone deficiency, commonly seen in children
- Prolactin
- May be mildly elevated due to the pituitary stalk effect
- Serum sodium, urine specific gravity, and osmolality
- Evaluates for diabetes insipidus (vasopressin deficiency)
- Cosyntropin stimulation test
- Performed when morning cortisol is equivocal or indeterminate to assess adrenal reserve
Treatment / Management
The treatment for craniopharyngiomas remains challenging because of their location, invasiveness, and proximity to adjacent neurovascular structures. Multiple modalities can be implemented in managing craniopharyngioma, including surgery, radiotherapy, and intracystic therapy. The choice of treatment, surgical approach, and extent of resection should be individualized for each patient. The patient's age, underlying medical comorbidities, tumor location, type and invasiveness, and, ultimately, neurosurgeon experience should be considered while determining the optimal treatment strategy.
Preoperative Management
Hormonal deficiency, specifically secondary adrenal insufficiency, and hypothyroidism, should be treated with glucocorticoid and thyroid hormone replacement before surgery. Glucocorticoid replacement is done with either hydrocortisone 20 to 30 mg in 2 to 3 doses or prednisone 5 to 10 mg in a single or divided dose. Levothyroxine can be used in cases of thyroid hormone deficiency. External ventricular drainage may be needed in cases presenting acutely due to hydrocephalus. Preoperative shunting should be used with caution as it may result in slit ventricles making transventricular approaches more difficult.
Neurosurgery
Surgical intervention is indicated to confirm diagnosis and relieve compression on neurovascular structures, which cause neurologic deficits, pituitary dysfunction, and hydrocephalus. The most common surgical approaches are endoscopic endonasal transsphenoidal (EET) or transcranial, depending on the location of the tumor.[30] Several grading systems have been developed based on the location of craniopharyngioma and its relation to surrounding structures to help decide on the best modality for surgery. Puget and colleagues classified tumors based on their hypothalamic involvement.[31] In their classification system, tumors were divided into grades 0-2, with grade 0 tumors having no hypothalamic involvement and predominantly occupying the subdiaphragmatic space. With these tumors, endoscopic, endonasal approaches are ideal. With grade 1 tumors, the tumor pushes or compresses the hypothalamus, and either endoscopic or open approaches can be used. With grade 2 craniopharyngiomas, the hypothalamus cannot be demarcated from the tumor due to tumor invasion. Due to the high risk of hypothalamic injury, endonasal approaches are not recommended with grade 2 tumors.[30](B2)
Kassam et al developed a separate classification system based on the location of the infundibulum to strategize the surgical approach.[32] Type I tumors are classified as preinfundibular, which are subchiasmatic tumors displacing the optic chiasm superiorly and posteriorly and can often be accessed via endoscopic, endonasal, or transplanum approaches. Type II tumors are transinfundibular, which can extend into the third ventricle and can be approached via the endonasal route, similar to type I tumors. Type III is retroinfundibular and can either extend superiorly into the third ventricle or inferiorly into the pontine cisterns. Type IV tumors are primarily located in the third ventricles. EET can be done in all types except type IV. The isolated third ventricular tumors are better approached with craniotomy and transcallosal, transcortical, or transventricular approaches.(B3)
Several studies have compared transcranial microsurgery and endoscopic endonasal surgery for craniopharyngiomas. Two retrospective studies on adult patients with craniopharyngiomas found a similar extent of resection between transcranial and endoscopic endonasal surgeries.[33][34] Both studies found higher rates of postoperative cerebrospinal fluid leaks in the endoscopic endonasal cohort and similar recurrence rates between both surgical approaches. Another retrospective study of pediatric patients showed endoscopic endonasal surgery was associated with higher rates of gross total resection and lower recurrence rates.[35] Furthermore, results from a meta-analysis including 22 studies comparing surgical approaches for craniopharyngiomas in adults and pediatric patients demonstrated lower tumor recurrence rates, better postoperative visual improvement, and lower occurrence of visual deterioration among patients undergoing endoscopic endonasal surgery.[36](A1)
A major dilemma during surgery is the decision to sacrifice the pituitary stalk in an attempt to achieve a gross total resection at the expense of pituitary dysfunction.[37] Results from a recent meta-analysis of 14 studies and 2074 patients showed a significantly higher risk of endocrine dysfunction after stalk sacrifice but no significant difference in the risk of recurrence or progression of disease.[38] Given these results, the pituitary stalk should be preserved when possible. In cases of primarily cystic tumors, placement of an Ommaya reservoir for repeated aspirations is a viable option.[39][40][41](A1)
Radiotherapy
Radiation therapy includes conventional external radiotherapy, proton beam therapy, and radiosurgery.[42] Radiation aims to decrease tumor burden while protecting essential neural structures. Proton therapy may provide better cognitive outcomes than photon therapy, which has similar survival outcomes.[43] Multiple reports have suggested decreased mortality with slightly reduced morbidity following radiation therapy. Despite this, radiation therapy has not been proven to reduce the recurrence rate. Therefore, it continues to be an adjuvant modality to neurosurgical intervention.[44][45] In cases of primarily cystic tumors, intracystic catheters can be introduced into the cyst, allowing for frequent aspiration of the cyst contents and reducing the size of the target for radiation.[46]
Intracystic Therapy
Brachytherapy is primarily used to treat purely cystic craniopharyngiomas.[47][48] Intracystic therapy with radioactive isotopes, bleomycin, and interferon-alpha has been used to induce tumor fibrosis and sclerosis.[49] A disadvantage of this option is the risk of severe neurotoxicity due to cystic leakage of the sclerosing substance.(A1)
Chemotherapy
While surgical resection is the mainstay of treatment for craniopharyngiomas, chemotherapy agents targeting BRAFV600E mutations can sometimes be used. A phase 2 study evaluated the safety and efficacy of the BRAK-MEK inhibitor combination of vemurafenib-cobimetinib in patients with BRAFV600E mutated papillary craniopharyngiomas.[50] In their cohort of 16 patients, 15 (94%) had at least a partial or better response to therapy. Results from other studies have reported using BRAF inhibition in newly diagnosed cases, in cases where patients refuse surgical treatment, or in cases of recurrent disease.[51][52][53](B3)
Hormonal Treatment
GH deficiency
Most patients requiring GH treatment have persistent GH deficiency and have not achieved their normal height velocity. Interestingly, some patients will attain normal height postoperatively without replacement. The period after surgery without any treatment is essential to identify the patients who will benefit from GH treatment. Even though GH treatment is relatively safe, there are some concerns about growth in residual tumors; thus, patients should be monitored closely when treated with GHs.
Gonadotropin Deficiency
The hormone replacement should be individualized depending on the age and growth of patients. Earlier treatment with steroids can lead to cessation of growth. In girls, a combination of estrogen and progesterone is given to induce puberty. The treatment usually starts with a very low dose of estrogen, with a gradual increase over time with periodic progesterone treatment to prevent uterine hyperplasia. In boys, testosterone treatment is started between 12 to 15 years, depending on their growth. Usually, patients are started on a smaller dose and gradually increased to the full adult dose. The current testosterone replacements available are intramuscular testosterone, given every 2 weeks, and gel preparation that is used daily.
Thyroid Stimulating Hormone Deficiency
The thyroid function test should be monitored postoperatively, as 29% to 85% of patients can develop hypothyroidism following surgery or radiation treatment. The ideal replacement is levothyroxine, an oral tablet taken daily. Before starting treatment, it is essential to ensure the adrenal axis is intact, as thyroid hormone replacement can increase the metabolic clearance of glucocorticoids and thus may cause an adrenal crisis.
Adrenocorticotropic Hormone Deficiency
Patients should be monitored postoperatively by checking morning cortisol, as more than 50% of children can be diagnosed with adrenal insufficiency later after surgery or radiation treatment. Children are usually treated with prednisone or hydrocortisone. The glucocorticoid replacement dose is 6 to 9 mg/m2 with dose adjustment with increasing age and weight.
Vasopressin Deficiency
Diabetes insipidus can develop in 70% of craniopharyngioma patients after surgery. Postoperatively, it is important to monitor patient urine output, plasma sodium, urine osmolality, and specific gravity. Desmopressin acetate, DDAVP, is the primary treatment in the form of an oral tablet or nasal spray.
Postsurgical Care
There should be close neurologic monitoring of patients after surgery for cerebral spinal fluid leaks, hemorrhage into the resection cavity, and the development of diabetes insipidus. Hormonal deficiency management is crucial after surgery. Stress dose steroids may be needed in patients in immediate postoperative care, depending on the type of surgery and presurgical hormonal evaluation. Careful hormonal monitoring by checking postoperative morning cortisol levels can decide the duration of glucocorticoid treatment. Monitoring sodium and urine osmolarity is important to monitor the development of diabetes insipidus. Thyroid hormone should be assessed in 1 to 2 weeks after surgery. Sex hormones and growth hormones can be evaluated at 3 months postoperatively. The anterior pituitary hormone replacement varies on a case-to-case basis.
Differential Diagnosis
The differential diagnosis for craniopharyngioma includes:
- Inflammatory conditions
- Pituitary abscess, lymphocytic hypophysitis, infundibulitis, histiocytosis, sarcoidosis, tuberculosis, and syphilis
- Congenital lesions
- Rathke cleft cyst, arachnoid cysts
- Other tumors
- Pituitary adenomas, primitive neuroectodermal tumors, hypothalamic hamartoma, germ cell tumors, epidermoid or dermoid tumors, meningioma, medulloblastoma, brainstem glioma, and lymphoma
- Vascular malformations
- Giant suprasellar carotid aneurysm, cavernous sinus hemangioma, and carotid-cavernous fistula [54]
Prognosis
The prognosis of craniopharyngiomas depends on the size, histologic type of tumor, surgical methodology, and the degree of hypothalamus and endocrine deficiencies. The overall survival rate of craniopharyngiomas approaches 80% to 95% at 10 years.[55][56][57] Craniopharyngiomas have a very high recurrence rate, with 1 study reporting 39.1% recurrence in adults with a median time to recurrence of 45 months.[58] Recurrence of the craniopharyngioma is most common at the primary site, but occasionally, metastatic foci may appear due to seeding during surgery.[59]
Complications
Complications related to the treatment of craniopharyngioma can occur after surgical resection, radiation, and/or chemotherapy. Some of the complications are as follows:
- Visual field disturbance and loss of vision
- Diabetes insipidus and hypernatremia
- Hydrocephalus
- Seizures
- Pituitary hormone disturbances
- Hypothalamic obesity
- Cerebral spinal fluid leak
- Cognitive dysfunction [60][61][62]
- Radiation-induced moyamoya arteriopathy [63]
- Development of secondary tumors after radiation
- Death
Deterrence and Patient Education
Primary prevention is impossible since craniopharyngiomas are congenital in origin and not associated with modifiable risk factors. However, early detection through prompt recognition of symptoms such as visual disturbances, headaches, growth retardation, and endocrine dysfunction is critical in minimizing long-term complications. Pediatricians, endocrinologists, and ophthalmologists play a vital role in identifying early warning signs, particularly in children presenting with delayed puberty, short stature, or unexplained weight gain. Regular monitoring of at-risk patients with appropriate imaging and endocrine evaluations can facilitate early intervention and prevent severe morbidity associated with tumor progression.
Patient education should focus on understanding the chronic nature of the disease and the potential long-term complications of both the tumor and its treatment. Patients and caregivers should be informed about the importance of regular follow-ups with endocrinology, neurosurgery, and neuroophthalmology to monitor for recurrence and manage hormonal deficiencies. Education on hormone replacement therapy, including signs of adrenal insufficiency, diabetes insipidus, and hypothyroidism, is essential for ensuring adherence to treatment and preventing life-threatening complications. Additionally, addressing concerns about hypothalamic obesity and mental health issues through dietary counseling, physical activity, and psychological support can significantly improve quality of life. Empowering patients with knowledge about their condition fosters proactive participation in their care and enhances long-term outcomes.
Enhancing Healthcare Team Outcomes
Managing craniopharyngiomas requires a highly coordinated, multidisciplinary approach to optimize patient-centered care, safety, and long-term outcomes. Clinicians, including neurosurgeons, endocrinologists, oncologists, and neuroophthalmologists, must work together to develop individualized treatment plans that balance tumor control with preserving neurological and endocrine function. Advanced clinicians and nurses are crucial in early symptom recognition, patient education, and postoperative monitoring. Pharmacists ensure appropriate hormone replacement therapy, manage medication interactions, and educate patients on adherence to lifelong treatments. Effective communication among team members is essential for timely intervention, particularly in addressing complications such as adrenal insufficiency, diabetes insipidus, and hypothalamic obesity.
Care coordination is vital in transitioning patients from acute care to long-term management. Regular interprofessional team meetings and standardized protocols help streamline communication, ensuring that all specialists remain informed of treatment progress and evolving patient needs. Nurses and case managers facilitate follow-up care, connecting patients with endocrinologists and rehabilitation services to manage the metabolic, cognitive, and psychological challenges associated with the disease. Patient safety is enhanced through structured education programs, equipping caregivers with the knowledge to recognize signs of hormonal crises and visual deterioration. By fostering collaboration across disciplines, healthcare professionals can improve team performance, reduce complications, and enhance patients' overall quality of life with craniopharyngiomas.
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