Craniopharyngioma

INTRODUCTION — Craniopharyngiomas are rare solid or mixed solid and cystic tumors that arise from remnants of Rathke's pouch along a line from the nasopharynx to the diencephalon [1]. Historically, these have also been referred to as "Rathke pouch tumors" or "hypophyseal duct tumors."

The epidemiology, pathology, diagnosis, management, and outcomes after treatment of craniopharyngiomas are reviewed here.

EPIDEMIOLOGY — In the United States, an estimated 350 new cases of craniopharyngioma are diagnosed each year, resulting in an age-adjusted incidence of 0.19 per 100,000 persons [2].

Craniopharyngiomas constitute approximately 1 to 3 percent of all brain tumors [3,4] and approximately 5 to 10 percent of brain tumors in children [4,5]. Elsewhere in the world, craniopharyngiomas are more common, particularly in Japan and some parts of Africa [6,7]. Craniopharyngiomas are approximately equally common in males and females.

There is a bimodal age distribution, with one peak in children between 5 and 14 years old and a second peak in adults between 50 and 75 years of age [3]. Adamantinomatous craniopharyngiomas are more common in children, while papillary craniopharyngiomas predominate in adults [8]. (See 'Pathology and molecular genetics' below.)

PATHOLOGY AND MOLECULAR GENETICS — Craniopharyngiomas usually arise along the pituitary stalk in the suprasellar region adjacent to the optic chiasm. A small percentage arises within the sella [9,10], and even fewer along the optic system or within the third ventricle [11,12].

Craniopharyngiomas are epithelial tumors. In the World Health Organization classification of central nervous system tumors, they are divided into two categories, adamantinomatous and papillary [13]. These histologically disparate types have distinct molecular genetics.

Adamantinomatous craniopharyngiomas are characterized by activation of the Wnt signaling pathway, and almost all harbor activating mutations in CTNNB1, the gene encoding β-catenin [14-16]. By contrast, papillary craniopharyngiomas commonly harbor mutations in the BRAF oncogene [16]. In the largest study to date, mutations in CTNNB1 were identified in 96 percent of 53 adamantinomatous tumors, and BRAF V600E mutations were identified in 94 percent of 39 papillary tumors [16].

Although benign histologically, craniopharyngiomas are locally aggressive and frequently shorten life; many clinicians consider them low-grade malignancies. Most contain both solid and cystic components. The cysts are filled with turbid fluid that contains cholesterol crystals.

The prognostic importance of tumor type is uncertain; older series have found that these two histologic subtypes behave similarly with respect to resectability, sensitivity to radiation, and overall survival [17,18].

CLINICAL PRESENTATION — Craniopharyngiomas grow slowly, and symptoms often are present for a year or more before the diagnosis is established [19,20]. A wide range of symptoms may be present. Symptoms reflect a tumor's precise location and its relationship to adjacent normal structures.

●Visual symptoms – Visual symptoms are frequent, and visual field deficits on formal ophthalmologic assessment are present in most patients. These result from compression of the optic chiasm or nerves; the specific deficit depends upon the growth pattern of the tumor.

●Endocrine abnormalities – Direct damage to or compression of normal structures can lead to a range of endocrine abnormalities. Frequently observed complications include arginine vasopressin deficiency (AVP-D, previously called central diabetes insipidus) and deficiencies of growth hormone, gonadotropin, thyroid-stimulating hormone, and adrenocorticotropic hormone in an estimated 75, 40, 25, and 25 percent of cases, respectively [5].

Growth failure, caused by either hypothyroidism or growth hormone deficiency, is the most common presentation in children. Sexual dysfunction is the most common endocrine manifestation in adults; almost 90 percent of men complain of erectile dysfunction, while most women have amenorrhea.

●Headache – Moderate to severe daily headaches are present in approximately 50 percent of patients at the time of diagnosis [21]. These may result from traction on pain-sensitive structures by the tumor itself, obstructive hydrocephalus from tumor compression of the third ventricle, or meningeal irritation by escaped cyst contents.

●Other symptoms – Craniopharyngiomas can also cause other generalized symptoms, such as depression and slowed cognition, independent of any hormone deficiency. The presumed cause is extension of tumor into the frontal lobes, striatal and thalamic areas, or limbic system. Nausea, vomiting, and lethargy can accompany pressure-related headaches.

DIAGNOSIS — At the time of diagnosis, craniopharyngiomas vary from small, solid, well-circumscribed masses to huge multilocular cysts that invade the sella turcica and displace neighboring cerebral structures.

Neuroimaging — Preoperatively, the diagnosis of craniopharyngioma is usually suggested by the presence of a suprasellar enhancing mass about the pituitary stalk on magnetic resonance imaging (MRI) and/or computed tomography (CT). The mass often compresses, displaces, and adheres to adjacent structures, including the optic nerves and chiasm, arteries of the Circle of Willis, pituitary gland, and hypothalamus; larger tumors can compress the third ventricle, brainstem, and frontal and temporal lobes (image 1 and image 2).

One or more cysts are present in approximately 75 percent of craniopharyngiomas. Calcification in the suprasellar region is seen in over 60 percent of patients with craniopharyngioma. A cystic, calcified parasellar lesion in a child is very likely to be an adamantinomatous craniopharyngioma. CT or plain skull radiographs can help distinguish adamantinomatous craniopharyngiomas from noncalcified suprasellar lesions, including papillary craniopharyngiomas, which are less likely to be calcified than adamantinomatous tumors [22].

Craniopharyngiomas must be distinguished from other tumors in the parasellar area (including pituitary macroadenoma, meningioma, optic glioma, germinoma, teratoma, lymphoma, metastasis), from nonneoplastic cysts (Rathke's, pars intermedia, and arachnoid), and from infiltrative disorders such as sarcoidosis and systemic histiocytosis [20]. (See "Causes, presentation, and evaluation of sellar masses", section on 'Cysts' and "Causes, presentation, and evaluation of sellar masses".)

Pretreatment evaluation — Since most patients with craniopharyngioma have at least partial hypopituitarism, endocrine testing, particularly of adrenal and thyroid function, is indicated before surgery. (See "Diagnostic testing for hypopituitarism" and "Determining the etiology of adrenal insufficiency in adults".)

A detailed neuroophthalmologic examination including visual field testing helps to determine the severity of compression of the optic pathways and establishes a presurgical baseline. (See "Causes, presentation, and evaluation of sellar masses", section on 'Visual defects'.)

MANAGEMENT — Historically, the optimal treatment of craniopharyngiomas has been controversial and included two basic approaches: aggressive surgery with an attempt to achieve complete resection at diagnosis versus a more conservative surgical approach that uses adjuvant radiation therapy (RT) to treat residual disease [23].

Major advances in neurosurgical techniques have significantly decreased the morbidity and mortality associated with resection, making aggressive resection feasible in more cases. At the same time, improvements in RT techniques have permitted more accurate delivery of radiation to the tumor target, while minimizing radiation damage to normal structures, and molecularly targeted therapies have emerged for papillary tumors. (See 'Surgical approach' below and 'Radiation therapy' below and 'Targeted therapy for BRAF-mutant tumors' below.)

An experienced multidisciplinary team (neurosurgery, radiation oncology, neuro-oncology, endocrinology, ophthalmology, neuroradiology, and neuropathology) is essential for the optimal treatment of both pediatric and adult patients with craniopharyngiomas [5,20,24].

Multidisciplinary planning — Suspected craniopharyngioma requires multidisciplinary input from neurosurgery, radiation oncology, and oncology for optimal treatment sequencing. With the discovery of effective targeted therapies for BRAF-mutant papillary craniopharyngioma, which accounts for the majority of craniopharyngiomas diagnosed in adulthood, it is particularly important to review cases of suspected craniopharyngioma preoperatively.

Surgical approach

High suspicion for BRAF-mutant tumor — When neuroimaging suggests craniopharyngioma, the patient has clinical characteristics suggestive of a papillary subtype (eg, adult age group, lack of tumor calcification), and severe, mass-related symptoms are not present, surgical options range from biopsy to gross total resection, and treatment decisions should be individualized with multidisciplinary input before surgery.

A transsphenoidal approach is often sufficient to obtain diagnostic tissue, and if papillary histology is confirmed, BRAF-targeted therapy is an option that can sometimes result in dramatic tumor reduction. This strategy potentially avoids the need for more aggressive surgery, radiation of larger fields, and their complications. (See 'Targeted therapy for BRAF-mutant tumors' below.)

On the other hand, use of BRAF-targeted therapy can be limited due to treatment toxicity and poor long-term tolerance. In addition, discontinuation of drug therapy is often followed by tumor regrowth. Thus, whereas BRAF-targeted therapy can help reduce aggressive neurosurgical risk, it does not replace the role of adjuvant radiation therapy, such that a safe gross total resection, when possible, is always preferred [25]. Caution should also be taken when combining BRAF-targeted therapy and cranial irradiation because of increased risk for neurologic toxicity [26,27].

Low suspicion for BRAF-mutant tumor — More aggressive surgery is indicated in almost all cases in which biopsy reveals an adamantinomatous craniopharyngioma or symptoms warrant relief of mass effect (eg, impending severe visual loss or brain herniation).

The goals of surgery are to establish the diagnosis, alleviate mass-related symptoms, and remove as much tumor as is safely possible. Complete resection may be limited by adherence of tumor to critical neural and vascular structures. Some neurosurgeons advocate cyst drainage to reduce neural compression and limited resection of solid tumor in anticipation of irradiation of residual tumor. Others advocate more aggressive surgery, arguing that the initial operation offers the best chance for surgical cure with the lowest risk of neurologic injury [25,28,29]. Gross total resections are durably curative without the need for additional radiation therapy and avoid radiation-associated late effects such as panhypopituitarism.

Preoperative management should include treatment of disease-related complications that could increase the risk associated with surgery:

●Endocrine function should be assessed and significant abnormalities corrected prior to surgery if possible. (See "Diagnostic testing for hypopituitarism" and "Treatment of hypopituitarism".)

●Significant peritumoral edema should be treated, and increased intracranial pressure should be controlled. (See "Evaluation and management of elevated intracranial pressure in adults" and "Management of vasogenic edema in patients with primary and metastatic brain tumors".)

●Hydrocephalus may require temporary cerebrospinal fluid (CSF) diversion through an external ventricular drain. Permanent shunting may be needed.

●Patients with a large cystic component of their tumor may require cyst aspiration prior to surgery to reduce mass effect or relieve obstructive hydrocephalus. (See 'Cyst management' below.)

The choice of treatment, the goals of surgery, and the surgical approach should be individualized for each patient. Considerations include the following: patient age, neurologic deficit, medical condition, and preference; tumor location, size, extension, consistency, and prior therapy; the institution's capabilities; and the surgeon's experience. The goals of surgery are usually to obtain pathologically diagnostic tissue, alleviate symptoms and neurologic deficits, relieve any obstructive hydrocephalus, decompress the optic nerves and chiasm, and remove as much of the tumor as possible without causing new neurologic or endocrine dysfunction.

Surgical strategy in children is particularly controversial. The benefit of gross total resection of craniopharyngioma in terms of quality of life in children is disputed [30,31]. This lack of certainty of benefit warrants cautious surgery, particularly in the region of the hypothalamus, since damage to this area from either preoperative involvement or surgery is a major predictor of poor quality-of-life outcomes [32,33]. Although more conservative surgery often results in residual tumor with the potential to regrow, the likelihood of regrowth can be reduced substantially by focal RT [34,35]. This benefit likely exceeds the risk of radiation-induced injury to the diencephalon, malignant change in the residual tumor or surrounding brain, or local scarring that might complicate any subsequent surgery.

Choice of surgical approach depends upon the location of the tumor. Intrasellar tumors are most readily removed transsphenoidally. An extended endonasal, endoscopic, transsphenoidal approach can access not just sellar tumors, but also suprasellar tumors including some that extend into the third ventricle (image 3) [28,36-38]. This approach is more difficult when the interval between the diaphragma sellae and optic chiasm is limited and is contraindicated for tumors restricted to the third ventricle. Some third ventricular tumors can be exposed via craniotomy, from below, through the lamina terminalis or, from above, through the foramen of Monro.

Other limitations of the extended endonasal approach include extension of tumor lateral to the internal carotid arteries or above the anterior communicating artery complex, regions that may be accessed by simultaneous pterional or subfrontal craniotomy, respectively [37].

Preoperatively, the relation of the tumor to the pituitary stalk and chiasm (pre- or postinfundibular and pre- or postchiasmal) should be noted; diffusion tensor imaging tractography may be helpful [39]. In all cases, the surgeon should seek to identify and preserve the pituitary stalk, avoid manipulation of the optic chiasm, and refrain from dissection of tumor invading the hypothalamus (picture 1). Even with these precautions, postoperative hypothalamic dysfunction can occur, particularly with retrochiasmatic tumors that involve the posterior hypothalamus. While several small retrospective studies suggest that rates of obesity and arginine vasopressin deficiency (AVP-D) may be lower in patients treated with more conservative surgical approaches [40-42], prospective studies with long-term follow-up are needed to better compare the full range of outcomes with various contemporary surgical and RT techniques.

Targeted therapy for BRAF-mutant tumors — All craniopharyngiomas should be tested for BRAF V600E mutations by immunohistochemistry or sequencing to determine whether targeted therapy is a rational option as first-line therapy or, for previously diagnosed and treated tumors, as therapy for recurrence. Nearly all papillary craniopharyngiomas have BRAF V600E mutations. (See 'Pathology and molecular genetics' above.)

For patients with newly diagnosed BRAF-mutant papillary craniopharyngioma, a trial of BRAF/mitogen-activated protein kinase kinase (MEK) inhibition can be considered before proceeding with definitive RT or an attempt at maximal resection. BRAF-mutant craniopharyngiomas are highly responsive to BRAF inhibition, typically within the first two to three months of therapy [22,43,44]. BRAF/MEK combination therapy (eg, vemurafenib plus cobimetinib or dabrafenib plus trametinib) is preferred because the MEK inhibitor reduces both off-target side effects and treatment resistance related to the paradoxical activation of the mitogen-activated protein kinase (MAPK) pathway seen with first-generation BRAF inhibitors.

After four to six cycles of combined targeted therapy, further treatment should be individualized after discussion of the potential risks and benefits of RT, surgery, continued targeted therapy, and observation. Any of these four options may be reasonable depending on clinical circumstances and the results of further studies.

This approach is supported by the results of a cooperative group trial of the Alliance for Clinical Trials in Oncology. In this multicenter single-arm phase 2 study, 16 adult patients (aged 33 to 83 years, median age of 49.5 years) with biopsy-confirmed BRAF V600E-mutant papillary craniopharyngioma (≥10 mm in diameter) and no prior therapy were treated with vemurafenib (960 mg orally twice daily) and cobimetinib (60 mg once daily on days 1 to 21 of every 28-day cycle) [43]. The protocol prespecified that patients would receive definitive surgery or radiation therapy after four cycles of vemurafenib plus cobimetinib, but exceptions were made for selected patients who appeared to have benefited from treatment, had serious risks for additional treatment, or declined subsequent therapy.

Overall, 15 out of 16 patients (94 percent) had a partial or complete volumetric response to four cycles of targeted therapy [43]. The one patient who did not respond discontinued therapy after only eight days due to toxicity. Decrease in both cystic and solid components was seen. Among responders, reduction in tumor volume ranged from 68 to 99 percent (median of 91 percent). At completion of the protocol-specified targeted therapy, eight patients received RT (six RT alone, one RT followed by surgery and one RT followed by dabrafenib), one patient continued vemurafenib plus cobimetinib off-protocol, and seven patients had no further therapy. Estimated progression-free survival rates at 12 and 24 months were 87 and 57 percent, respectively, and overall survival at 24 months was 100 percent. Among the seven patients who stopped therapy, six had no progression at a median follow-up of 23 months. Grade 3 adverse events occurred in 12 of 16 patients (75 percent), most commonly rash, and there were two grade 4 adverse events (hyperglycemia and elevated creatine kinase).

Radiation therapy — RT is used to treat patients with residual disease after partial surgical resection or targeted therapy or to treat disease that has recurred despite surgery and/or targeted therapy [45].

RT techniques — Contemporary RT techniques permit greater treatment precision and conformity. These approaches decrease, but do not eliminate, long-term toxicity by limiting the exposure of surrounding normal tissues to ionizing radiation [46]. Treatment techniques providing highly conformal, image-guided radiation include stereotactic radiotherapy (SRT) [45,47-49], intensity-modulated RT (IMRT), and proton beam therapy [50-53].

●Stereotactic techniques – SRT and stereotactic radiosurgery (SRS) utilize head fixation to establish a patient-specific coordinate system for imaging, treatment planning, and delivery. Imaging of applied fiducial markers or facial contours permits localization of the patient's head and tumor within this coordinate system, allowing precise delineation of the target treatment volume and accurate description of the planned radiation field. (See "Stereotactic cranial radiosurgery".)

SRT uses a fully fractionated treatment schedule, usually approximately 30 fractions to 54 Gy, to minimize damage to normal structures, while allowing coverage of a relatively large target volume. SRS uses one to five fractions; it is an acceptable alternative to more extensively fractionated radiotherapy for small tumors or small focal postoperative residuals that are safely distant from the optic pathway to not risk visual injury. For both SRT and SRS, priority is taken to keep the dose within the tolerance of the optic nerves, chiasm, and tracts.

●Intensity-modulated RT – IMRT is a sophisticated software planning technique that uses dynamic delivery of radiation to optimize the delivery of radiation to irregularly shaped volumes. This technique can be added to SRT or SRS to shape the beam to the irregular contours of the tumor. (See "Radiation therapy techniques in cancer treatment", section on 'Intensity-modulated radiation therapy'.)

●Proton beam RT – Heavy particle irradiation techniques such as proton beam use charged particles rather than photons to deliver high doses of radiation to the target volume while limiting the "scatter" dose received by surrounding tissues. There is minimal radiation exposure beyond the Bragg peak, where the protons come to a halt and deliver their energy. This can be advantageous in treating tumors very near critical structures [53]; however, the margin of this benefit is far lower with contemporary higher precision stereotactic localization and conformal photon technique with IMRT. (See "Radiation therapy techniques in cancer treatment", section on 'Particle therapy'.)

Radiation dose — For fractionated treatment schedules using conformal RT techniques, standard dose is 54 Gy at 1.8 Gy per fraction to best balance safety of normal tissue radiation exposure with sufficient dose to be durably effective. In a retrospective series, the recurrence rate was significantly higher in patients receiving ≤54 Gy compared with higher doses (50 versus 15 percent) [54].

Patients with cystic craniopharyngioma undergoing radiotherapy must be reimaged routinely during the course of treatment. Cysts can enlarge during radiation and necessitate revision of the radiotherapy plan.

Cyst management — Attempts to decrease cyst size are often indicated when a cyst compresses visual or hypothalamic structures or causes symptomatic obstruction of the third ventricle. Surgical removal of the tumor is the most definitive treatment. Cysts recurrent after surgery may be treated in several ways.

Aspiration — Percutaneous aspiration of cyst contents can alleviate symptoms; intermittent aspiration may be needed when cyst excision is not feasible [55,56]. This can be facilitated by placement of an Ommaya reservoir [57].

Intracystic irradiation — Solitary or multicystic tumors can be treated with intracavitary irradiation via stereotactically applied radioisotopes [58-63]. Beta-emitting isotopes such as yttrium-90 (90Yt), rhenium-186 (186Rh), and phosphorus-32 (32P) are preferred because of the limited penetrance of the emitted energy and their relative ease of handling.

Intracystic chemotherapy — Alternatively, intracystic instillation of chemotherapeutic and immunologic agents has been tried [64]. In one series, intracystic bleomycin produced complete remission of disease in five of 17 children and a median progression-free interval of 1.8 years with limited toxicity [65]. Intracystic installation of interferon alpha has also been used [66-68]. This approach may postpone the need for RT or aggressive surgery.

Disease control — Complete resection is the ideal outcome of surgery. Untreated residual tumor will likely resume enlargement with solid tumor growth and/or cyst expansion. Improvements in surgical techniques have increased the frequency with which a complete resection can be achieved without excessive morbidity or mortality [28,69,70]. However, the benefits of surgery must be balanced against treatment-related morbidity [38]. (See 'Surgical approach' above.)

RT, widely used as an adjuvant following subtotal resection, significantly reduces the risk of local recurrence [71-76]. The impact of adjuvant RT on overall survival is less clear; RT may be less effective as salvage therapy for recurrent disease. There are no randomized trials that compare adjuvant RT with observation after surgery followed by salvage RT for recurrent disease.

The following reports from large series illustrate the range of findings using contemporary surgical and RT techniques:

●A meta-analysis showed better outcomes with the extended endoscopic endonasal approach than with craniotomy or a limited transsphenoidal approach [77]. Total tumor resection was more likely; improvement of vision was more common; and rates of worsening of vision, pituitary dysfunction, AVP-D, hemorrhage, and mortality were lower. The rate of CSF leakage, however, is higher with endonasal approaches. A separate study found higher rates of postoperative AVP-D and lower rates of visual improvement with transcranial resections; hypothalamic injury was common with both approaches [78].

●In one series of 65 pediatric tumors treated surgically, mostly through a transsphenoidal route with intent of complete removal, gross total resection was achieved for 98 percent of tumors treated initially and for 25 percent of recurrent tumors [28,38]. The rate of recurrence after initial gross total resection was 7 percent. Newly diagnosed obesity occurred in 9 and 21 percent of patients after initial and recurrent surgery, respectively [28,38].

●Seventy-five patients treated for craniopharyngioma at a single institution over a 27-year period underwent an attempt at gross total excision [71]. Eighteen of the 27 patients in whom only a subtotal resection was possible received adjuvant RT. RT was also given to 22 patients with a local relapse following surgery alone. At a median follow-up of 7.6 years, the 10-year local control rate was significantly better for the patients with subtotal resection plus RT than for the 57 patients treated with surgery alone, 48 of whom originally had a complete resection (84 versus 42 percent). The overall survival rate for the entire cohort was 85 percent.

●Of 121 patients treated between 1963 and 2002, 19 underwent gross total removal, 84 partial resection, and 9 cyst evacuation [72]. All patients who received gross total resection were free of recurrence at 10 years. Among those managed with partial resection, the 10-year recurrence-free rates were 77 and 38 percent, with and without postoperative RT, respectively.

●SRT (52.2 Gy in 1.8 Gy fractions) was used to treat 40 patients (28 with recurrent disease, 12 as an adjuvant after surgery) [47]. At a median follow-up of 98 months, local control was 100 percent at 10 years and overall survival was 89 percent.

●Forty-six patients with craniopharyngioma underwent 51 courses of treatment with SRS for residual or recurrent craniopharyngioma (median tumor volume 1.0 cm³) [49]. At a mean follow-up of over five years, the five-year overall and progression-free survival rates were 97 and 92 percent, respectively.

Treatment complications — Numerous complications can accompany treatment of craniopharyngioma. These may be specific to surgery or radiation therapy, reflect the combined adverse effects of the two, or represent aggregate effects of the tumor and its treatment. Deficits can be caused by injury to critical neural structures by tissue manipulation; vascular compromise during surgery; or radiation-induced neural toxicity, necrosis, or vasculopathy [79].

Surgery-specific complications include infection, bleeding, and CSF leakage [80]. Radiation-specific complications include delayed induction of atherosclerosis and vascular anomalies. The potential for treatment to cause devastating deficits mandates thoughtful coordinated planning by a multidisciplinary team of experienced specialists.

Endocrine — Endocrine abnormalities can arise from or be exacerbated by treatment; these likely contribute to the increased mortality of patients with craniopharyngioma [79,81]. They reflect injury to the hypothalamus, pituitary stalk, or both.

●Altered pituitary function, present in most patients, can manifest as panhypopituitarism or isolated hypogonadism, hypothyroidism, adrenal insufficiency, and/or growth hormone deficiency [82,83]. For patients treated in childhood, the 10-year cumulative risk of each of these exceeds 70 percent [42,83]. (See "Clinical manifestations of hypopituitarism" and "Diagnostic testing for hypopituitarism" and "Treatment of hypopituitarism".)

Growth hormone replacement initiated in childhood increases height and does not appear to have an adverse impact on overall survival and progression-free survival [84]. Growth hormone administration beginning one year after diagnosis may be associated with early improvements in quality of life when measured three years after diagnosis [85].

●Hypothalamic endocrine dysfunction can include hyperphagia, disabling obesity [86,87], metabolic syndrome with type 2 diabetes mellitus, nonalcoholic liver disease [88], disorders of sleep and temperature regulation, and AVP-D. (See "Arginine vasopressin deficiency (central diabetes insipidus): Etiology, clinical manifestations, and postdiagnostic evaluation" and "Arginine vasopressin deficiency (central diabetes insipidus): Treatment" and "Obesity in adults: Etiologies and risk factors", section on 'Hypothalamic obesity'.)

Neurologic — Common nonendocrine neurologic complications include:

●Visual deficits – Most patients have visual field deficits prior to treatment. These may be exacerbated acutely by surgery-induced stroke or chronically by radiation-induced optic neuritis or vasculopathy. Diplopia can result from injury to oculomotor nerves during surgical approaches.

●Neurocognitive deficits – Diminished awareness, slowed thought, and memory loss can occur. Severe memory loss can follow injury to the fornix due to some cranial approaches or excessively aggressive dissection of tumor from the hypothalamus bordering the third ventricle [79,89,90].

●Behavioral problems – Apathy, lethargy, and depression can reflect primary neural loss or secondary hormonal deficiency [91].

Vascular abnormalities — Radiation therapy can increase risk of ischemic vascular disease and development of cerebrovascular anomalies [81,82]. In a retrospective series of 123 patients with craniopharyngioma treated with multimodality therapy, 14 patients experienced transient ischemic attack or stroke; of these, two were in the immediate postoperative period and 12 occurred at a median of 4.4 years after radiation [82]. A small cross-sectional cohort study observed a trend suggesting that long-term replacement of growth hormone may reduce the risk of stroke [92].

A variety of vascular abnormalities can follow irradiation of a craniopharyngioma, particularly in children. In one series, among 20 patients who underwent imaging following radiation treatment, six had abnormalities, including temporal cavernomas, moyamoya syndrome, aneurysms, and decreases in arterial caliber [92,93].

Cerebrovascular complications of cranial irradiation are reviewed in more detail separately. (See "Delayed complications of cranial irradiation", section on 'Cerebrovascular effects'.)

Secondary tumors — RT to treat craniopharyngiomas has been associated with secondary development of meningioma and malignant glial tumors [82,83,94]. (See "Risk factors for brain tumors", section on 'Ionizing radiation'.)

RECURRENT DISEASE — Most tumor recurrences are local; surgery, whether used initially or deferred, may be indicated, as may be radiosurgery, if enlarging focal solid disease rather than cyst expansion is the problem [95]. In addition, molecularly targeted therapy is an option in BRAF-mutant tumors at recurrence [96-98]. (See 'Targeted therapy for BRAF-mutant tumors' above.)

Malignant histologic transformation is rare but has been reported, usually after multiple recurrences and radiation therapy (RT) [99,100]. Remote recurrences can occur, possibly as a consequence of seeding through the cerebrospinal fluid (CSF) during surgery [101-104]. Morbidity and mortality are higher with treatment of recurrent disease than with initial therapy [24].

POSTTREATMENT FOLLOW-UP — There are no evidence-based guidelines for follow-up after initial therapy. Key features of patient management include:

●Neuroimaging with magnetic resonance imaging (MRI), initially every 3 to 12 months, depending upon the residual tumor, tumor cyst, and concern for potential early progression. When radiation therapy is used adjuvantly, a durable effect often takes months to set in. The duration of imaging follow-up depends upon the extent of initial surgery, the presence or absence of residual tumor, and symptomatology. Cases of recurrence after decades of tumor quiescence suggest the need for long-term follow-up.

●Monitoring of endocrine function with replacement hormone therapy as needed.

●Formal assessment of visual function including visual field testing postoperatively and annually thereafter.

PROGNOSIS — The long-term prognosis following treatment is influenced both by the ability to control tumor and the development of treatment-related complications. Rates of 10-year overall survival range from 80 to 96 percent [72,82,83].

Despite this, late mortality is increased in patients even without tumor progression; this may reflect complications of treatment, particularly in survivors of childhood craniopharyngioma [105].

In one series of 41 patients treated over 37 years, there were nine deaths (22 percent) overall [106]. One of these occurred between 10 and 20 years, and three occurred more than 20 years after presentation. These four deaths resulted not from uncontrolled tumor progression but from arginine vasopressin deficiency (AVP-D), pontine infarction, panhypopituitarism, and liver failure.

Another population-based study of 307 patients with craniopharyngioma followed for a median of nine years found that individuals with craniopharyngioma had a three- to fivefold increase in expected mortality compared with that of the general population [81]. The major contributors to excess mortality were cerebrovascular disease (standardized mortality ratio [SMR] 5.1), type 2 diabetes mellitus (SMR 5.6), myocardial infarction (SMR 2.1), and severe infection (SMR 5.9).

Many series have relatively short follow-up; older studies with longer follow-up may not be informative regarding the results of newer surgical and radiation therapy (RT) techniques. Patients treated with contemporary techniques may fare better.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Primary brain tumors".)

SUMMARY AND RECOMMENDATIONS

●Epidemiology – Craniopharyngiomas are rare suprasellar brain tumors arising from the remnants of Rathke’s pouch. There is a bimodal age distribution, with peak incidence between 5 and 14 years and later between 50 and 75 years of age. (See 'Epidemiology' above.)

●Pathology and genetics – Histologically, craniopharyngiomas are either adamantinomatous (more common in childhood) or papillary (predominant in adults). All tumors should be tested for BRAF V600E mutations by immunohistochemistry or sequencing. Nearly all papillary craniopharyngiomas have BRAF V600E mutations. (See 'Pathology and molecular genetics' above.)

●Clinical features – Craniopharyngiomas are slow-growing tumors that usually arise along the pituitary stalk in the suprasellar region adjacent to the optic chiasm. Common presenting symptoms include visual changes, endocrine abnormalities, and headache. (See 'Clinical presentation' above.)

Neuroimaging shows a suprasellar enhancing mass (image 1), often cystic and, in the case of adamantinomatous tumors, calcified (image 2). (See 'Neuroimaging' above.)

●Multidisciplinary planning – Individuals should be managed by a multidisciplinary team experienced in the treatment of craniopharyngioma that includes neurosurgery, radiation oncology, neuro-oncology, endocrinology, ophthalmology, neuroradiology, and neuropathology. (See 'Management' above.)

●Surgical management – When neuroimaging suggests craniopharyngioma in a patient with clinical characteristics suggestive of a papillary subtype (eg, adult age, lack of tumor calcification) and there is an intent to offer BRAF-targeted therapy to lessen need for risky surgery and large radiation fields, biopsy or conservative resection is an alternative to upfront aggressive surgery. However, decisions should be individualized, since BRAF therapy does not replace the role of adjuvant radiation and is sometimes poorly tolerated, and gross total resections, when safe, can be curative and obviate the need for adjuvant therapy of any kind. (See 'High suspicion for BRAF-mutant tumor' above.)

For all other patients, initial management involves surgical resection to establish diagnosis, alleviate mass-related symptoms, and remove as much tumor as is safely possible. (See 'Low suspicion for BRAF-mutant tumor' above.)

●Postoperative therapy

•BRAF-mutant tumors – For most patients with newly diagnosed BRAF-mutant papillary craniopharyngioma who have residual disease after surgical management, we suggest treatment with BRAF-targeted therapy (eg, vemurafenib/cobimetinib or dabrafenib/trametinib) and/or adjuvant radiation therapy (RT), rather than watchful waiting (Grade 2C). Adjuvant RT improves local control and may be associated with less morbidity than use as a salvage therapy. (See 'Radiation therapy' above.)

For patients who elect BRAF-targeted therapy, treatment decisions after four to six cycles should be individualized after discussion of the potential risks and benefits of RT, surgery, continued targeted therapy, and observation. (See 'Targeted therapy for BRAF-mutant tumors' above.)

•All other tumors – For most other patients, postoperative decisions are individualized based on the extent of tumor residual, patient age and comorbidities, and the potential risks of RT. RT after subtotal resection reduces the risk of recurrence. Some patients require additional procedures to manage symptomatic cysts. (See 'Radiation therapy' above and 'Cyst management' above.)

●Treatment complications – A wide range of endocrine and neurologic complications are observed in patients with craniopharyngioma following treatment; these likely contribute to the increased mortality of patients with craniopharyngioma and thus the rationale for lifelong surveillance for these patients. (See 'Treatment complications' above.)

●Prognosis – The long-term prognosis following treatment is influenced both by the ability to control tumor and the development of treatment-related complications. In long-term follow-up studies, rates of 10-year overall survival range from 80 to 96 percent. (See 'Prognosis' above.)