Craniopharyngioma Treatment & Management

Postsurgical follow-up should be planned in 1-2 weeks for all patients. Patients with subtotal resections and candidates for external beam radiation therapy should start radiation within 3 weeks of surgery. Patients with either complete resections or completed radiation should be seen every 3 months for the first postsurgical year, every 6 months for the second and third years, and yearly thereafter.

Each follow-up visit should include (1) a brain MRI that should be used for comparison with previous films and (2) correlation of the MRI with the clinical examination and neurocognitive testing results.

As a rule, consider neurocognitive testing for (1) presurgery and postsurgery patients and (2) patients who have undergone subtotal resection followed by radiation. All patients should have neurocognitive testing whenever declining performance (eg, school, work) is a concern or clinical examination reveals worsening neurocognitive deficits (eg, problem solving, language, memory, apraxia).^{[18, 24]}

In some patients, deficits encountered are related to radiation injury. These could be sorted out easily by the specific MRI findings and neurocognitive testing results. Subsequently, specific treatments can be employed. Close monitoring of endocrine symptoms, accompanied by confirmatory laboratory tests, is recommended for all patients. Most patients require several adjustments of their supplemental hormonal therapy during their postsurgical/postradiation phase and even years later. Prior radiotherapy treatment was reported to not compromise the beneficial effects of growth hormone replacement therapy.^[25]

Aggressive preventive management of long-term, multisystem morbidities is key for long-term survival. A multiteam, comprehensive approach is strongly recommended. Panhypopituitarism was reported to be present in almost 90% of patients followed up for more than 10 years. Long-term endocrinologic follow-up and monitoring are strongly recommended.

At 10 years, other highly prevalent morbidities have been found to be neurologic (49%), psychosocial (47%), and cardiovascular (22%). Female sex is reported as an independent predictor of increased cardiovascular, neurologic, and psychosocial morbidity. Long-term follow-up should include appropriate endocrine replacement^[26] (including estrogen in premenopausal women) and aggressive control of cardiovascular risk factors (blood pressure, weight, lipids, and glucose).

Recurrence

Immunohistochemical studies and case reports caution on the possibly higher incidence of recurrence in patients receiving growth hormone and/or sex hormone replacement, as some craniopharyngiomas express insulinlike growth factor receptors (IGF-1Rs), estrogen receptors (ERs), and progesterone receptors (PRs).

However, despite reported sporadic expression of IGF-1Rs in 2 large, retrospective reviews (including children and adults) in which the mean treatment duration was 6 years and the mean follow up was approximately 10 years, no evidence was found to suggest increased recurrence rates in patients who received growth hormone supplementation.^{[12, 13]} Close imaging follow-up (every 4-6 wk) and clinical monitoring would be indicated if sex hormone and/or growth hormone replacement is pursued.

Essentially, 2 main management options are available for craniopharyngioma: (1) attempt at gross total resection or (2) planned limited surgery followed by radiotherapy.

However, no consensus of opinion exists concerning the appropriate management of craniopharyngiomas, and no guidelines have as yet been established by the Neuro-oncology Section of the American Academy of Neurology.

Most of the accepted management strategies are from retrospective reviews; no prospective, randomized clinical trials have been conducted to compare the various therapeutic modalities.

Although no consensus exists on the treatment modalities for craniopharyngiomas, most authors maintain that successful management is determined by the ability to preserve independent social functioning, by symptomatic recurrence, and by survival.

Neuropsychological deficits represent the major limiting factor for independent social functioning because (1) patients often can overcome minor neurologic deficits and (2) hormone-repleting therapies are widely available. The degree of psychosocial impairment correlates directly with the degree of hypothalamic injury sustained at the time of surgery.

Attempts at employing systemic chemotherapy in the treatment of craniopharyngiomas have been unsuccessful. New systemic biologic therapies are currently under investigation (eg, interferon (IFN) alpha-2a for progressive or recurrent craniopharyngiomas) and have had interesting results.

Inflammatory cytokines and biomodulation

Several inflammatory cytokines have been shown to be elevated in the craniopharyngioma cyst fluid in comparison with the CSF. Interleukin (IL)–1alpha and tumor necrosis factor (TNF)–alpha levels were significantly elevated, although these elevations did not reach 10-fold the levels in the CSF. The concentration of IL-6 was over 50,000 times greater in the cystic fluid than in the CSF.^[19] This supports the hypothesis that biomodulation of the cytokine profile could lead to long periods of stability and even tumor regression.

IFN-alpha exerts diverse influences mainly on cytokine antagonists and soluble adhesion molecules. It has been shown to play a role in the treatment of craniopharyngioma in some limited trials, after systemic use and local, direct intracystic use.^[20]

Gross total surgical removal is the treatment of choice for craniopharyngioma; however, it can be associated with morbidity and mortality rates as high as 20% (excluding endocrinopathies) and 12%, respectively. Recurrence rates can be as high as 20%; a serious potential for psychosocial deficits exists in patients with hypothalamic injury.

The surgical approaches for resection of craniopharyngioma include the standard pterional approach, the orbitocranial approaches, and the subfrontal, transsphenoidal, and transcallosal approaches. At times, a combination of approaches is necessary.

Potential perioperative morbidities include the following:

• Seizures
• Visual deficits - Including blindness
• Hypothalamic injury
• Stroke
• Cerebrospinal fluid (CSF) leakage

Endocrinopathy is common. Permanent diabetes insipidus occurs in 68-75% of adults and 80-93% of children. Replacement of 2 or more of the anterior pituitary hormones is necessary in 80-90% patients. Obesity occurs in 50% of patients.

Recurrence/progression following failed gross total or subtotal resection is common and occurs in 75% of patients. Recurrence usually is identified 2-5 years following resection.

Tumor adhesion to surrounding vascular structures represents the most common cause of incomplete tumor removal. Fusiform dilatations of large, surrounding vessels have been reported after attempts at radical dissection of the tumor capsule; they injure vasa vasorum, thereby weakening the adventitia. Tumor adhesion is the result of local inflammation.

Some authors propose a plan of limited surgery, with postoperative radiotherapy as the management paradigm of choice for craniopharyngioma. Goals of this approach are (1) pathologic confirmation of the tumor and (2) surgical decompression of the optic chiasma. Surgery is followed by external beam radiation, at a dose of 5400-5500 cGy delivered at 180 cGy/fraction.

The incidence of tumor progression after planned limited surgery and radiotherapy ranges from 12-25% and is similar to that seen with failed gross total resection and radiotherapy (4-25%).

Radiotherapy delivered at recurrence (salvage radiotherapy) is effective, with posttreatment progression rates of 29%. Recurrence following radiotherapy has been associated with a 50-80% mortality rate.

Thus, the optimal approach should consider total removal safe (ie, no hypothalamic injury) or otherwise combine a subtotal resection (ie, removal of as much tumor as possible with no hypothalamic injury) with postoperative radiotherapy.

For selected patients with suprasellar craniopharyngiomas, an endonasal extended endoscopic approach could provide a viable alternative to transcranial approaches.^{[21, 22]}

Other approaches that can be useful in the management of giant craniopharyngioma, especially at the time of recurrence, include (1) intermittent aspiration by stereotactic puncture or Ommaya reservoir placement, (2) intracystic injection of bleomycin,^[23] and (3) internal irradiation with radioisotopes. The latter 2 treatment modalities have been reported to control the tumor cysts in 90-100% of cases.

In general, the 10-year survival rate for craniopharyngiomas is 90%, and the 20-year survival rate for pediatric craniopharyngiomas is approximately 60%.