Continuing Education Activity

Craniopharyngioma is a rare, virtually benign tumor of the central nervous system (CNS). It is a partly cystic embryonic malformation that can occur in the sellar/parasellar region and can produce a wide array of symptomatology such as headaches, nausea and vomiting, visual disturbances, and endocrine disturbances. It represents a special challenge for the clinicians that treat it; these clinicians commonly include neurosurgery, neuro-ophthalmology, neurology, endocrinology, and pediatrics. The challenge is due to the tumor's ability to adhere to the surfaces that surround it. For this reason, it is extremely difficult to control, and it is also notorious for its high rates of recurrence. This activity reviews the etiology, presentation, evaluation, and management of craniopharyngioma and reviews the role of the interprofessional team in evaluating, diagnosing, and managing the condition.

Objectives:

• Describe the etiology of craniopharyngioma.
• Review the necessary evaluation process for craniopharyngioma.
• Summarize the management options for craniopharyngioma.
• Explain the importance of improving care coordination on the interprofessional healthcare team to enhance the delivery of care for patients with craniopharyngioma.

Introduction

Craniopharyngiomas are rare, benign tumors of the central nervous system. Craniopharyngiomas are epithelial tumors that typically arise in the suprasellar area of the brain, extending to involve the hypothalamus, optic chiasm, cranial nerves, third ventricle, and major blood vessels. It can produce a wide array of symptoms such as headaches, nausea, and vomiting, visual and endocrine disturbances. It represents a special challenge for the physicians treating it; these physicians commonly include neurosurgeons, neuro-ophthalmologists, neurologists, endocrinologists, and pediatricians. Curative surgeries are extremely difficult due to their location and infiltration into the surrounding structures. Further, the quality of life is compromised due to the development of multiple complications, including panhypopituitarism, visual problems, obesity, and mental disorders.[1][2][3][4]

Etiology

There are two major theories of the development of craniopharyngioma: the embryonic theory and the metaplastic theory. These two theories correlate with the two histologic subtypes of craniopharyngiomas, that is, adamantinomatous craniopharyngioma (ACP) and papillary craniopharyngioma (PCP).[5]

The embryonic theory is related to the development of ACP, which is a more common subtype and can affect all age groups. During embryogenesis, there is an outpouching of the ectodermal roof of the stomodeum. This outpouching, known as Rathke's 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 not total, and remnants of ectodermal cells can be present. These embryonic cells can proliferate around the extension of the craniopharyngeal duct and develop into a craniopharyngioma. Somatic mutation in the CTNNB1 is proposed to be responsible for ACP development. CTNNb1 mutation is a point mutation in exon 3 leading to excessive β-catenin protein, thus activating the WNT signaling pathway leading to cell proliferation, invasion, and development of a tumor.

The metaplastic theory is related to the development of PCP, which is primarily seen in adults. The adenohypophyseal cells of the pars tuberalis can undergo metaplasia and result in the formation of squamous cell nests, which further proliferates and leads to PCP. Somatic mutation in BRAF has been associated with PCP. BRAF activated the mitogen-activated protein kinase(MAPK) pathways, which are usually upregulated in cancer.

Epidemiology

Craniopharyngioma has an incidence of 0.5 to 2 cases per million persons per year. Craniopharyngiomas can be recognized at any age. It is generally considered a pediatric disease accounting for 1.2 to 4% of all intracranial tumors; however, approximately half of the craniopharyngiomas are diagnosed in adults. It has a classical bimodal age distribution, with an increased incidence rate in 5 to 14 years and 50 to 74 years of age. There is no statistical difference in the incidence based on gender, race, and geographical location. Familial cases of craniopharyngioma have been reported only in 2 families.

Craniopharyngioma has a very high recurrence rate of approximately 50%. It also has high survival rates (83% to 96% five-year survival and 65% to 100% 10-year survival) but also carries similar rates of morbidity, with almost all patients developing some sequelae.

Pathophysiology

The most common location of craniopharyngioma is the sellar/suprasellar region, with 95% of craniopharyngiomas having a suprasellar component. Its location defines its pathophysiology. Craniopharyngiomas can compress normal pituitary tissue and result in pituitary deficiencies, particularly of the anterior pituitary hormones. It can also compress the optic chiasm and/or optic nerves and cause different degrees and types of visual disturbances, from blurry vision to blindness. It can also present with hydrocephalus secondary to third ventricle compression. In cases of significant suprasellar extension, non-specific symptoms of intracranial hypertension such as a headache, nausea, and vomiting can also occur. Cases of isolated oculomotor nerve and abducens nerve palsies have been described.

Most craniopharyngiomas are supplied by blood from the anterior circulation.

Recurrence of the craniopharyngioma is most common at the primary site, but occasionally metastatic foci may appear as a result of seeding during surgery.

Histopathology

Craniopharyngiomas are histologically benign World Health Organization (WHO) grade I tumors.  There are two histologic subtypes of craniopharyngiomas: adamantinomatous and papillary.

Adamantinomatous craniopharyngioma (ACP) is primarily seen in pediatric cases but can be seen in adults. They have solid and cystic parts. The solid part is characterized by dense nodules and trabeculae of squamous epithelium bordered by a palisade of columnar epithelium, sometimes referred to as 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.

Papillary craniopharyngioma (PCP) is commonly seen in adults. They are characterized as well-differentiated squamous epithelium lacking surface maturation, with occasional goblet cells and ciliated epithelium. Calcifications are rare in the papillary type. The papillary craniopharyngiomas are well-circumscribed compared to the adamantinomatous type, and invasion of surrounding brain tissue is much less common.

History and Physical

Craniopharyngiomas are slow-growing tumors thus are usually diagnosed late when the patient develops compressive symptoms. Symptoms usually indicated the location of tumors and proximity to surrounding structures.

Headaches

Headaches are reported in approximately 50 % of patients. Headaches may be due to increased intracranial pressure (ICP) with associated nausea and vomiting or meningeal irritation from the cystic fluid.

Visual Symptoms

62% to 84% of craniopharyngiomas patients will present with visual symptoms. The most common visual disturbance encountered is temporal hemianopsia due to optic chiasm compression. The dysfunction of the optic pathway is present in 50-75% of patients. 

Hormonal Deficiency

At the time of the initial presentation, approximately 40 to 87% of patients present with at least one hormonal deficit. In adults, 40% of patients will have gonadotroph deficiency presenting as amenorrhea in females and loss of libido and erectile dysfunction in males. 85% of adult patients will have growth hormone (GH) deficiency presenting as non-specific symptoms like weight gain, central obesity, and fatigue. Approximately 25 % of patients will have adrenocortical hormone (ACTH) deficiency leading to weight loss, generalized arthralgia, dizziness, and hypotension. TSH deficiency is present in 25% of patients with symptoms of weight gain, fatigue, cold intolerance, and constipation. Vasopressin deficiency, also known as diabetes insipidus, is reported in approximately 20% of patients presenting with symptoms of polyuria and polydipsia.

Evaluation

The evaluation of craniopharyngioma requires an interprofessional approach with evaluation by an endocrinologist, neuro-opthalmologist, and neurosurgeon.

Imaging

Craniopharyngioma is diagnosed with computerized tomography (CT) and or magnetic resonance imaging (MRI) during the evaluation of visual symptoms. MRI is the standard of care in identifying craniopharyngiomas or any other pituitary tumors as it provides better information on the tumor, its location, and association to the surrounding structure. The cystic area is visible on both modalities, but calcification is primarily seen with CT imaging. Craniopharyngioma is heterogeneous in texture; the combination of solid, cystic, and calcification components is a clue to its diagnosis on imaging modalities. ACP is primarily large irregular with 90% calcification and a cystic area, while PCP is mostly solid and rarely with cysts and calcifications.

Visual Exam

A complete visual exam, including acuity and visual field, should be done by a neuro-opthalmologist in patients with visual disturbances.

Endocrine Evaluation

All patients should be evaluated for hormonal deficiencies. Laboratory tests should include fasting morning cortisol, ACTH, TSH, free T4, follicle-stimulating hormone (FSH), estradiol (females), testosterone (males), GH, insulin-like growth factor-1, prolactin, serum sodium, and urine specific gravity and osmolality. Dynamic testing like a cosyntropin stim test can be done in selected patients where morning cortisol is equivocal or indeterminate.

Treatment / Management

The treatment for craniopharyngiomas is challenging because of their location, invasiveness, and proximity to adjacent neurovascular structures. Multiple modalities can be implemented in the management of craniopharyngioma, including surgery, radiotherapy, and intracystic therapy. The choice of treatment, surgery type, and extent should be individualized for each patient. The patient's age, underlying medical co-morbidities, tumor location, type and invasiveness, and ultimately neurosurgeon experience should be considered while deciding the treatment strategy. There is no consensus on the best treatment regimen.[6][7][8][9][10][11]

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 divided doses or prednisone 5 to 10 mg in a single or divided dose. Levothyroxine is the best way to replace thyroid hormone deficiency.

A temporary or permanent shunt may be needed to drain cerebrospinal fluid for treatment of hydrocephalus.

Surgery

Surgical intervention is indicated to confirm the diagnosis, tumors causing neurologic deficits, pituitary dysfunction, and hydrocephalus. The most common surgical approaches are endoscopic endonasal transsphenoidal (EET) or transcranial, depending on the location of craniopharyngioma. Extension of resection is a matter of debate. Gross total resection has been associated with an increased incidence of post-surgical deficits, with no change in the recurrence rates.

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. Kassam et al. had a classification system based on the infundibulum to strategize the surgical approach. Type I tumors are pre-infundibular, which are sub chiasmatic tumors displacing the optic chiasm superiorly and posteriorly. Type II tumors are trans-infundibular, which can extend into the third ventricle. Type III is retro-infundibular which can either extend superiorly into the third ventricle or inferiorly into the pontine cisterns. Type IV tumors are primarily located in the third ventricles. ETT can be done in all types except type IV. The isolated third ventral tumors are better approached with craniotomy and transcallosal, transcortical, or trans-ventricular approaches. ETT should be avoided in very large tumors, mostly solid with calcification and vascular invasiveness.

Postsurgical Care

There should be close neurologic monitoring of patients after surgery for cerebrospinal fluid(CSF) leaks.

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 are important to monitor the development of diabetes insipidus. Thyroid hormone should be assessed in 1 to 2 weeks after surgery. The sex hormone and GH can be assessed at 3 months postoperatively. The anterior pituitary hormone replacement varies on a case-to-case basis.

Radiotherapy

Radiation treatment is used in patients with residual disease or to prevent recurrences. Radiation therapy includes conventional external radiotherapy, proton beam therapy, stereotactic radiotherapy, radiosurgery, and brachytherapy. The goal of radiotherapy is to decrease tumor burden while protecting essential neural structures. Specific Gy doses have been designated for every radiation modality. 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.

Intracystic Therapy

Intracystic therapy is primarily used for purely cystic craniopharyngioma. Toxic substances like radioactive isotopes, bleomycin, interferon-alpha are used in intracystic therapy to produce tumor fibrosis and sclerosis. This method has been reported to produce significant cyst shrinkage, but there is limited data on its use and support. A disadvantage of this option is that severe neurotoxicity can occur in some cases due to cystic leakage of the sclerosing substance. 

Differential Diagnosis

• Arachnoid cyst
• Brain tumor
• Epidermoid tumor
• Langerhan cell histiocytosis
• Leptomeningeal cancer
• Meningitis
• Migraine
• Multiple sclerosis
• Optic gliomas
• Pituitary adenoma
• Pseudotumor cerebri
• Rathke’s cleft cyst

Prognosis

The prognosis of craniopharyngiomas is dependent on the size, histologic type of tumor, surgical methodology, and the degree of hypothalamus and endocrine deficiencies. The overall survival rate of craniopharyngiomas is 80 to 95% at 5 years. The prognosis is good in young individuals and poor for individuals over the age of 65. Females tend to have additional morbidity that includes stroke, adverse cardiac events, and psychosocial deficits.

Pearls and Other Issues

1. Craniopharyngiomas are low histologic malignant tumors arising along the craniopharyngeal duct. 
2. There are two histologic subtypes, adamantinomatous craniopharyngioma (ACP) and papillary craniopharyngioma (PCP). Both of these have different age distribution, MRI appearances, and somatic mutations.
3. The treatment of craniopharyngiomas is primarily surgery and radiotherapy.
4. The prognosis of craniopharyngioma is good, but the quality of life is low due to hypothalamic and endocrine deficiencies.

Enhancing Healthcare Team Outcomes

Craniopharyngiomas are rare benign tumors of the central nervous system (CNS). These patients usually present to the primary care provider with a wide array of symptomatology such as headaches, nausea and vomiting, visual disturbances, and endocrine disturbances. It represents a special challenge for the physicians that treat it; these physicians commonly include neurosurgeons, neuro-ophthalmologists, neurologists, endocrinologists, and pediatricians. Specialty trained nurses in perianesthesia, operating room, and critical care are necessary for care. The interprofessional team is essential for optimum outcomes. The challenge is due to the tumor's ability to adhere to the surfaces that surround it. For this reason, it is extremely difficult to control, and it is also notorious for its high rates of recurrence. However, the outcomes in most people are good. [12][13] [Level 5]