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. Craniopharyngiomas constitute approximately 1 to 3 percent of all brain tumors [2,3] and approximately 5 to 10 percent of brain tumors in children [3,4]. Elsewhere in the world, craniopharyngiomas are more common, particularly in Japan and some parts of Africa [5,6]. 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 [2]. Adamantinomatous craniopharyngiomas are more common in children, while papillary craniopharyngiomas predominate in adults [7]. (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 [8,9], and even fewer along the optic system or within the third ventricle [10-12].
Although benign histologically, craniopharyngiomas frequently shorten life and should be considered low-grade malignancies. Most contain both solid and cystic components. The cysts are filled with turbid fluid that contains cholesterol crystals.
Craniopharyngiomas are epithelial tumors. In the World Health Organization classification of central nervous system tumors, they are divided into two categories, adamantinomatous and papillary [7]. 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 [13-15]. By contrast, papillary craniopharyngiomas commonly harbor mutations in the BRAF oncogene [15]. 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 95 percent of 39 papillary tumors [15].
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 [16,17].
CLINICAL PRESENTATION — Craniopharyngiomas grow slowly, and symptoms often are present for a year or more before the diagnosis is established [18,19]. 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 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 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 [4].
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 [20]. 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, 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 mass on magnetic resonance imaging (MRI) and/or computed tomography (CT).
Calcification in the suprasellar region is seen in 60 to 80 percent of patients with craniopharyngioma, and one or more cysts are present in approximately 75 percent. A cystic calcified parasellar lesion is very likely to be a craniopharyngioma (image 1 and image 2). CT or plain skull radiographs can help distinguish adamantinomatous craniopharyngiomas from noncalcified suprasellar lesions. Papillary craniopharyngiomas frequently lack calcification [21].
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 [19]. (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 "Diagnosis 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'.)
TREATMENT — 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 used radiation therapy (RT) to treat residual disease [22].
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. (See 'Surgery' below and 'Radiation therapy' 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 [4,19,23].
Surgery — Surgery is indicated in almost all cases. The goal of surgery is to establish the diagnosis, alleviate mass-related symptoms, and remove as much tumor as is safely possible. Some neurosurgeons advocate a strategy of reduction of neural compression by cyst drainage and limited resection of solid tumor in anticipation of irradiation of residual tumor. Many others argue that the initial operation offers the best chance for surgical cure when complete resection can be accomplished with low risk of neurologic injury [24].
Preoperative management should include treatment of disease-related complications that may be present and can 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".)
●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 required.
●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.
Treatment strategy in children is particularly controversial. The benefit of gross total resection of craniopharyngioma in terms of quality of life in children is disputed [25,26]. 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 [27,28]. Although this more conservative surgical strategy frequently results in residual tumor with the potential to regrow, the likelihood of regrowth can be reduced substantially by focal RT [29,30]. 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 [24,31-33]. 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 [32].
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 [34]. 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. 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 diabetes insipidus may be lower in patients treated with more conservative surgical approaches [35,36], prospective studies with long-term follow-up are needed to better compare the full range of outcomes with various contemporary surgical and RT techniques.
Radiation therapy — RT is used to treat patients with residual disease after a partial surgical resection or to treat disease that has recurred following what was initially thought to be a gross total resection [37].
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 [38]. Treatment techniques providing highly conformal, image-guided radiation include stereotactic radiotherapy (SRT) [37,39-41], intensity-modulated RT (IMRT), and proton beam therapy [42-44].
●Stereotactic techniques – SRT and stereotactic radiosurgery (SRS) utilize head fixation that establishes 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 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. For both SRT and SRS, care must be taken to keep the dose within the tolerance of the optic nerves, chiasm, and tracts.
●Intensity-modulated RT – IMRT is a three-dimensional (3D) technique that uses complex treatment planning and dynamic delivery of irradiation to optimize the delivery of radiation to irregularly shaped volumes. This technique can be added to 3D-conformal or SRT (whether delivered by photons or protons) 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 is particularly advantageous in treating tumors very near critical structures. (See "Radiation therapy techniques in cancer treatment", section on 'Particle therapy'.)
Radiation dose — For fractionated treatment schedules using conformal RT techniques, doses above 54 to 55 Gy significantly improve the likelihood of local tumor control compared with lower doses [45-47]. In a retrospective series, the recurrence rate was significantly higher in patients receiving ≤54 Gy compared with higher doses (50 versus 15 percent) [45].
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 — Techniques that decrease cyst size are generally 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 has been used to alleviate symptoms, and intermittent aspiration may be recommended when total excision is not feasible [48,49]. An alternative is placement of an Ommaya reservoir for intermittent aspiration of a cyst that cannot be completely resected [50].
Intracavitary irradiation — Solitary or multicystic tumors can be treated with intracavitary irradiation via stereotactically applied radioisotopes [51-56]. 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.
Intracavitary chemotherapy — An alternative approach to intracavitary irradiation uses bleomycin [57]. Experience is more limited than with intracavitary irradiation. In one series of 17 children, intracystic bleomycin was well tolerated, with five complete remissions and a median progression-free interval of 1.8 years [58]. Intracavitary interferon alfa has also been used at selected centers [59-61]. This approach may have a role in delaying RT or aggressive surgery.
Disease control — Complete surgical resection is the goal of initial treatment, and improvements in surgical techniques have increased the frequency with which a complete resection can be achieved without excessive morbidity or mortality [24,62,63]. However, the benefits of surgery must be balanced against treatment-related morbidity [33]. (See 'Surgery' above.)
RT is widely used as an adjuvant following subtotal resection, and this approach significantly reduces the risk of a local recurrence [64-69]. The impact of adjuvant RT on overall survival is less clear, probably reflecting the effectiveness of RT as salvage therapy for recurrent disease. There are no randomized trials that compare adjuvant RT with observation 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 [70]. Total tumor resection was more likely; improvement of vision was more common; and rates of worsening of vision, pituitary dysfunction, diabetes insipidus, hemorrhage, and mortality were lower. The rate of CSF leakage, however, is higher with endonasal approaches. A separate study found higher rates of postoperative diabetes insipidus and lower rates of visual improvement with transcranial resections; hypothalamic injury was common with both approaches [71].
●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 [24,33]. 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 [24,33].
●In 75 patients treated for craniopharyngioma at a single institution over a 27-year period, all patients underwent an attempt at gross total excision [64]. Postoperative RT was given to 18 of the 27 in whom only a subtotal resection was possible. RT was also given to 22 patients who experienced 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 a subtotal resection plus RT compared with the 57 patients treated with surgery alone, 48 of whom originally had a complete resection (84 versus 42 percent). The overall survival for the entire cohort was 85 percent.
●In 121 patients treated between 1963 and 2002, 19 underwent gross total removal, 84 partial resection, and 9 cyst evacuation [65]. All of the patients able to undergo 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.
●SRT (52 Gy in 1.8 Gy fractions) was used to treat 40 patients (28 with recurrent disease, 12 as an adjuvant after surgery) [39]. 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) [41]. 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
Endocrine — A wide range of endocrine complications are observed in patients with craniopharyngioma following treatment; these likely contribute to the increased mortality of patients with craniopharyngioma [72]. Endocrine abnormalities are due in part to the original tumor but can be exacerbated by treatment.
●Panhypopituitarism is present in most patients and can be manifested by hypogonadism, hypothyroidism, adrenal insufficiency, and/or growth hormone deficiency [73]. (See "Clinical manifestations of hypopituitarism" and "Diagnostic testing for hypopituitarism" and "Treatment of hypopituitarism".)
Growth hormone replacement that is initiated in childhood results in increases in height without impact on overall survival and progression-free survival when compared with children not receiving growth hormone [74]. Growth hormone administration beginning one year after diagnosis may be associated with early improvements in quality of life when measured at three years postdiagnosis [75].
●Hypothalamic dysfunction can cause disabling obesity, disorders of temperature regulation, sleep disorders, or diabetes insipidus. (See "Clinical manifestations and causes of central diabetes insipidus" and "Treatment of central diabetes insipidus (vasopressin deficiency)" and "Obesity in adults: Etiologies and risk factors", section on 'Hypothalamic obesity'.)
●Other morbidity can reflect complications of obesity, including metabolic syndrome, type 2 diabetes mellitus, and nonalcoholic liver disease [76].
Neurologic — Common neurologic complications include:
●Neurocognitive deficits, particularly among patients with hypothalamic involvement [77,78]
●Hypothalamic obesity [79,80] (see "Obesity in adults: Etiologies and risk factors", section on 'Hypothalamic obesity')
●Sleep disorders and a disrupted circadian rhythm [81,82]
●Behavioral problems [83]
Visual — Most patients have visual deficits prior to treatment. These may be exacerbated by either surgery or RT.
Vascular abnormalities — Patients may also be at increased risk for cerebrovascular disease as a consequence of therapy. A variety of vascular abnormalities can follow radiation of a craniopharyngioma, particularly in children. As an example, in one series of 20 patients who underwent imaging following treatment, six had abnormalities, including temporal cavernomas, moyamoya syndrome, aneurysms, and decreases in arterial caliber [84].
Ischemic cerebrovascular disease can also occur [72,73]. 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 receipt of radiation [73]. A small cross-sectional cohort study observed a trend suggesting that long-term replacement of growth hormone may reduce the risk of stroke [85].
Secondary malignancies — The use of RT to treat craniopharyngiomas has been associated with the secondary development of meningioma and malignant glial tumors [73,86]. (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 [87]. In addition, molecularly targeted therapy may be an option in BRAF-mutant tumors [88,89].
Malignant histologic transformation is rare but has been reported, usually after multiple recurrences and radiation therapy (RT) [90,91]. Remote recurrences can occur, possibly as a consequence of seeding through the cerebrospinal fluid (CSF) during surgery [92-95]. Morbidity and mortality are higher with treatment of recurrent disease than with initial therapy [23].
Targeted therapy in papillary tumors — Papillary craniopharyngiomas should be tested for BRAF V600E mutations by immunohistochemistry or sequencing to determine whether targeted therapy is a rational option for recurrent or progressive disease. Nearly all papillary craniopharyngiomas have BRAF V600E mutations. (See 'Pathology and molecular genetics' above.)
Clinically relevant partial and complete responses to BRAF and/or mitogen-activated protein kinase kinase (MEK) inhibitors have been reported in patients with recurrent or progressive tumors despite standard therapies. Based on a review of six patients, clinical and radiographic responses to BRAF and/or MEK inhibition (eg, dabrafenib plus trametinib, vemurafenib) tend to occur quickly, within the first three months of therapy [21]. A multicenter phase 2 study of vemurafenib plus cobimetinib is ongoing (NCT03224767) [96].
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 annually. The duration of imaging follow-up depends upon the extent of initial surgery, the presence or absence of residual tumor, and symptomatology, but 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. In a series of 121 cases, the 10-year survival rate following presentation was 90 percent when nontumor-related deaths were excluded [65]. In another large series, 10-year progression-free and overall survival rates were 48 and 80 percent, respectively [73].
Despite this, late mortality appears to be increased in patients without tumor progression and may be related to complications of treatment, particularly in survivors of childhood craniopharyngioma. As an example, in a series of 41 patients treated over a 37-year period, there were nine deaths (22 percent) overall [97]. Three of these occurred more than 20 years after presentation, and one occurred between 10 and 20 years. None of these four were directly related to tumor progression. The reported causes of death in these four cases were uncontrolled diabetes insipidus, pontine infarction, panhypopituitarism, and liver failure.
These observations were further supported by a population-based study of 307 patients with craniopharyngioma followed for a median of nine years [72]. Individuals with craniopharyngioma had a three- to fivefold increase in expected mortality compared with the general population. 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, and longer duration of follow-up is necessary to assess results. However, long-term studies often utilized older surgical and radiation therapy (RT) techniques, and patients treated with contemporary techniques may have better outcomes.
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
●Management of the patient with a craniopharyngioma (image 1 and image 2) involves a balance between controlling the disease and minimizing the side effects of treatment. (See 'Treatment complications' above.)
●Individuals should be managed by a multidisciplinary team with experience in the treatment of craniopharyngioma. The team should include neurosurgery, radiation therapy (RT), neuro-oncology, endocrine, ophthalmologic, neuroradiologic, and neuropathologic expertise. (See 'Treatment' above.)
●The initial management usually involves neurosurgical resection, with the goal of removing as much of the tumor as is possible without inducing severe deficits. (See 'Treatment' above.)
●For patients in whom a complete resection of tumor is not feasible, early postoperative RT is typically provided to establish local control. (See 'Treatment' above.)
●All papillary craniopharyngiomas should undergo testing for a BRAF mutation. BRAF inhibitors such as vemurafenib with or without a mitogen-activated protein kinase kinase (MEK) inhibitor (such as trametinib) are an option for patients with progressive or recurrent disease for which additional radiation or surgery are not feasible. (See 'Targeted therapy in papillary tumors' above.)
