Approach Considerations
Surgical treatment is indicated in most cases of craniopharyngioma, but surgeons have often approached this tumor with either an aggressive attempt at gross total resection of the tumor or a more conservative approach with a planned subtotal removal of the tumor followed by radiation therapy (RT). Contemporary radiation techniques deliver radiation more accurately, thus preserving the important anatomic structures around or near the tumor.
The decision for either approach should take into consideration the following characteristics of the tumor:
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Its anatomic location
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Its size
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The extent to which it is invading nearby structures
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Its nature
The most common indication for surgery is neurologic compromise from tumor mass effect. In children, hypothalamic and endocrine dysfunction may develop before visual defects are noticed. Obesity and lethargy are common in children with craniopharyngiomas. In general, any mass lesion in the pituitary sella and suprasellar area should undergo a biopsy or resection, if feasible. RT is indicated in recurrence or in the treatment of residual tumor. [33]
Surgery is contraindicated in patients with cardiac or respiratory abnormalities that make the risk of general anesthesia unacceptably high. Moreover, patients who take chronic anticoagulation medication must cease medication and demonstrate normal coagulation studies prior to surgery. Asymptomatic patients or those with a small tumor may be monitored with serial magnetic resonance imaging (MRI). A small tumor in the pituitary region without mass effect or endocrine dysfunction may also be monitored with serial MRI.
The question of whether to perform a gross total excision or to perform a subtotal resection followed by RT remains the largest divide in the treatment of craniopharyngiomas. Retrospective series support both philosophies. Surgical judgment must temper the enthusiasm for gross total removal at all costs.
The use of three-dimensional (3D) conformal radiation treatment (3D CRT), stereotactic radiosurgery (SRS), stereotactic RT (SRT), and intensity-modulated RT (IMRT) may allow treatment of small tumor residua with little risk of neurologic deficit. The development of endoscopic techniques has placed greater emphasis on minimally invasive approaches, but this should not rule out the use of the surgical techniques that the surgeon feels most comfortable with. [34, 35]
Medical Therapy
Advances in medical therapies for craniopharyngiomas have been aided by the identification of mutations specific to particular tumor subtypes. Adamantinomatous craniopharyngiomas (ACPs) often display mutations of beta-catenin, causing Wnt activation and alterations of the MEK/ERK pathway. [36] In the papillary craniopharyngioma (PCP) subtype, the vast majority of tumor cells have been found to overexpress the oncogene BRAF-V600E. [37] These mutations lead to overactivation of the MAPK pathway in select basal cells surrounding fibrovascular cores. [38]
Several algorithms have been proposed for distinguishing subtypes on the basis of MRI data alone. [39, 40, 41]
Drugs targeting beta-catenin and the downstream MAPK pathway have largely been studied in vitro; however, studies examining the use of BRAF inhibitors in PCPs, either alone or in combination with MEK inhibitors, have yielded promising clinical results.
Numerous case reports have shown BRAF inhibitors to be efficacious for reducing tumor size. A reduction of tumor volume on the order of 70-90% has been demonstrated in multiple patients receiving dual therapy with BRAF and MEK inhibitors. [42, 43, 44, 45, 46, 47, 48] The Alliance phase 2 trial is studying the efficacy of dual treatment in patients with PCP.
The promising data from these clinical trials suggest that neoadjuvant treatment of craniopharyngiomas should be considered in appropriate patients. Pretreatment of craniopharygiomas prior to surgical resection may be found to be advantageous as more data are collected.
Endocrine abnormalities often exist in patients with craniopharyngiomas. Hormonal replacements are administered as needed. There remains a need for further data regarding improvement of endocrine dysfunction in patients treated with targeted therapies.
Surgical Therapy
Choice of surgical approach
The initial surgical decision concerns the approach to the craniopharyngioma. If the predominant portion of the tumor is intrasellar, the approach is usually transsphenoidal. Often, the suprasellar component can be delivered into the sella and evacuated. Furthermore, the transsphenoidal approach is well tolerated by patients and is preferable to a craniotomy, when feasible. [49, 50, 51, 52, 26, 53, 54, 55] Comparative analyses of outcomes after expanded endoscopic endonasal transsphenoidal resection and after craniotomy have found similar extents of resection and rates of progression-free survival (PFS). [56]
If the pituitary sella is not enlarged, the transsphenoidal approach generally is not preferred. A craniotomy is usually necessary when the predominant component is suprasellar, though certain suprasellar masses may be located through an extended transsphenoidal approach. Technologic developments in optics and instrumentation have permitted many transsphenoidal procedures to be done exclusively through the endoscope. Specialized training is needed in these techniques, but in some instances, even large tumors in the suprasellar space can be safely removed or debulked. [57, 58, 59, 60]
The pterional craniotomy is the standard craniotomy approach to suprasellar lesions because it allows good visualization of the optic nerves, chiasm, and surrounding structures. Variations of this craniotomy have been proposed that include resection of the orbital rim and zygoma so as to provide a more defined view of the skull base and thereby allow better access to the superior aspects of this tumor. These approaches lend themselves to less frontal-lobe retraction in order to visualize the operative site.
A subfrontal approach is appropriate for lesions that lie anterior to the optic chiasm, but this may be difficult to determine preoperatively. Under rare circumstances, a transcallosal approach is necessary when the tumor is entirely within the third ventricle. The drawback to this approach is the inability to identify the optic chiasm and pituitary stalk early in the dissection.
Cystic tumors are amenable to either a transsphenoidal approach or a pterional craniotomy. The solid components often adhere to the optic chiasm or hypothalamus and, therefore, may be difficult to remove in their entirety.
Cyst aspiration combined with intracavitary phosphorus-32 (32P) instillation is an alternative to traditional surgical resection (see the video below). Good long-term control of tumor growth has been demonstrated; however, a tumor with significant solid components is not likely to respond to 32P. [61] Intracystic chemotherapy with bleomycin has also been tried, with some success in short-term reduction of cyst size. [62] Intracavitary therapy requires that an Ommaya reservoir be placed into the cyst. Care must be taken to ensure that the catheter tip openings are in the cyst itself and that there is no spillage of cyst contents or injected material outside the cyst wall.
Preoperative grading
In an attempt to balance the advantages of an aggressive surgical resection against the risk of significant morbidity, a preoperative grading system (for children) was proposed. This system considered the extent of invasion of the hypothalamus by the tumor, as follows [63] :
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Type 0 - The tumor represents no hypothalamic involvement
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Type 1 - The tumor distorts or elevates the hypothalamus, but the latter is still visible
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Type 2 - The hypothalamus is no longer visible
Consequently, some proposed that a gross total resection be attempted in type 0 and type 1 tumors and that a subtotal resection be attempted in a type 2 tumor, leaving only the hypothalamic component. Although this grading system was developed in a pediatric population, applying it to an adult population is certainly feasible. Some evidence exists, however, that the craniopharyngiomas that arise in adults are less likely to invade the hypothalamus.
A subsequent classification system proposed by Kassam et al used a scheme that divided tumors according to their suprasellar extension, based on the endoscopic expanded endonasal approach (EEA), as follows [59] :
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Type I - Preinfundibular
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Type II - Transinfundibular (extending into the stalk)
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Type III - Retroinfundibular, extending behind the gland and stalk, and having two subdivisions (IIIa, extending into the third ventricle; and IIIb, extending into the interpeduncular cistern)
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Type IV - Isolated to the third ventricle and/or optic recess and inaccessible via an endonasal approach
Preparation for surgery
Preoperative workup includes an endocrinologic evaluation, particularly to exclude hypoadrenalism and hypothyroidism, both of which increase surgical mortality. Dexamethasone may be started prior to surgery to decrease edema. [64]
Operative details
Successful transsphenoidal resection of a craniopharyngioma requires generous removal of the contents of the sella turcica. A nasoseptal flap is first harvested and placed in the choana. Using a binostral approach allows for a larger sphenoidotomy to expose the landmarks of the opticocarotid recess, the planum sphenoidale, and the clival recess.
Adequate suprasellar decompression occurs when the arachnoid membrane surrounding the tumor descends into the operative field. Cerebrospinal fluid (CSF) leakage occurs if the arachnoid is disrupted. By utilizing the infrachiasmatic corrodor, lesions extending into the suprasellar space can be removed. [65] A retrospective study by Stapleton et al suggested that the risk of CSF leakage in pediatric patients may be higher with an EEA. [66] A three-layer technique is often employed for skull-base reconstruction, utilizing a fat graft, fascia lata, and a nasoseptal flap.
The goal of a craniotomy is gross total removal of the tumor with preservation of the optic apparatus and pituitary stalk. Understanding the anatomy in this region is key to accomplishing this goal. The optic chiasm is nearly always elevated, and the pituitary stalk is usually displaced posteriorly. The stalk may be identified by the striate pattern of portal vessels along its surface. The lamina terminalis may have to be opened for access into the third ventricle. The goal of tumor removal must not outweigh the need for preservation of neural structures; therefore, it is advisable to leave undisturbed a tumor that is densely adherent to the optic apparatus, the anterior cerebral artery (ACA), or the hypothalamus.
Because long-term tumor control is generally excellent with RT following subtotal tumor removal, a conservative approach to tumor resection is usually advised. [67] In some patients, however, a good cleavage plane exists between tumor and brain, and a true complete resection can be accomplished. Surgical judgment is crucial in the assessment of this possibility.
Radiation Therapy
RT is indicated in patients who underwent a subtotal resection of craniopharyngioma or who are experiencing a recurrence. Types of RT include SRS and fractionated external beam radiation therapy (EBRT).
SRS techniques are based on localization of the target through stereotactic frame coordinates (attached to the head, as with the Gamma Knife) or non–frame-based techniques (as with the CyberKnife). Small tumors can be treated with a single fraction of radiation that delivers a high dose with rapid falloff to minimize the dose to surrounding structures. A larger target volume or proximity to the optic nerve and chiasm may necessitate use of fractionated SRS techniques designed to minimize damage to healthy structures. The dose delivered is usually limited by the optic chiasm, which ideally should receive less than 10 Gy.
EBRT uses 3D planning to deliver radiation with a margin around the tumor. As many as 30 fractions may be used to deliver an effective total dose while keeping daily doses low. The tumor recurrence rate is higher when the total dose is less than 54 Gy, and complications increase with doses higher than 62 Gy. [7, 68, 69]
Astradsson et al prospectively studied the use of fractionated SRT in 16 adult patients with craniopharyngioma and found it to be relatively safe. [70] The tumor control rate was acceptable; no new endocrinopathy developed, and only a single case of radiation-induced optic neuropathy occurred.
Data have been published to support the concept of subtotal resection followed by RT as an effective therapy that is equal to gross total resection with regard to outcome but has fewer complications. [71]
Complications
The most common complications are related to injury of the adjacent neural structures. Vision may worsen because of unavoidable manipulation of the optic apparatus. [72]
Postoperatively, many patients demonstrate hypopituitarism. In order to offset this, they are usually given physiologic doses of hydrocortisone as well as a dexamethasone taper to decrease the edema associated with the surgical approach.
Diabetes insipidus may develop and may have to be treated with fluid replacement and, occasionally, vasopressin or its synthetic analogue, desmopressin. Some patients have diabetes insipidus as well as disruption of their thirst sensation. These patients pose a difficult management problem and are at high risk for developing hypernatremia. Injuries to the hypothalamus can cause other behavioral changes, including caloric balance disturbance, memory disturbance, and changes in affective behavior.
In rare cases, development of radiation-induced gliomas may occur. This long-term complication has a latency period of greater than 10 years, frequently involves the temporal lobe, and has been predominantly reported in patients who underwent conventional fractionated RT in their childhood. [73]
Long-Term Monitoring
Performing a full postoperative endocrine evaluation as well as repeated imaging studies is advisable. MRI is typically performed immediately (≤ 48 hours) after the operative procedure, at approximately 3 months, and annually thereafter. Long-term follow-up also includes visual-field and pituitary hormone testing.
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Coronal MRI shows a craniopharyngioma in the suprasellar space that causes compression of the optic nerves and chiasm.
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Sagittal MRI shows a cystic craniopharyngioma in the suprasellar space with extension into the third ventricle.
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Axial MRI shows a craniopharyngioma cyst that contains proteinaceous fluid in the third ventricle. The cyst fluid appears hyperintense.
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Dissection of craniopharyngioma cyst with aspiration.
