Chemotherapy advances in craniopharyngioma

From Craniopharyngioma, Pediatrics: General Medicine

Chemotherapy advances in craniopharyngioma

Although the use of chemotherapy to treat craniopharyngioma is still under investigation, several approaches have been studied, including intracavitary irradiation and carmustine-impregnated wafers.

Introduction
Background

Craniopharyngiomas are histologically benign neuroepithelial tumors of the CNS that are predominately observed in children aged 5-10 years. These tumors arise from squamous cell embryologic rests found along the path of the primitive adenohypophysis and craniopharyngeal duct. Although histologically benign, these tumors frequently recur after treatment. In addition, because they originate near critical intracranial structures (eg, visual pathways, pituitary gland, hypothalamus), both the tumor and complications of curative therapy can cause significant morbidity. These characteristics have led to various treatment approaches, and disagreement continues regarding optimal treatment in children with this disease. Evidence suggests that adult craniopharyngiomas are histologically and biologically different from pediatric craniopharyngiomas; however, only childhood craniopharyngiomas are discussed in this article.
Pathophysiology

Pediatric craniopharyngiomas are believed to arise from cellular remnants of the Rathke pouch, which is an embryologic structure that forms both the infundibulum and anterior lobe of the pituitary gland. Its path of development extends from the pharynx to the floor of the sella turcica; not surprisingly, these tumors have been identified extensively in suprasellar, parasellar, and ectopic locations. Typically, the tumors arise within the sella or adjacent suprasellar space. Symptoms are caused by mass effects on adjacent normal intracranial structures.
Frequency
United States

Craniopharyngiomas are relatively rare, representing 6-10% of intracranial malignancies in children and adolescents (approximately 2-3 cases per 1,000,000 children). A bimodal distribution peak has been reported, with one peak at age 5-14 years and the other at age 65-74 years. More than 300 cases are reported in the United States annually, and roughly one third of these involve children aged 0-14 years.1, 2, 3 Craniopharyngiomas are the most common childhood tumor that occur in the sella-chiasmatic region.4
International

The Childhood Cancer Registry of Piedmont, Italy estimates an incidence of 1.4 cases per million children per year in keeping with reports from other Western countries. Higher incidence rates have been observed in Asia and Africa with 5.25 cases per million children reported in Japan in one series5.
Mortality/Morbidity

Previous studies have shown relatively good outcomes, with 10-year overall survival rates of 86-100% among patients who underwent gross total resection. Subtotal resection or recurrence treated with surgery and radiation therapy carry 10-year overall survival rates of 57-86%. The perioperative mortality rate after primary surgical intervention has been estimated to be 1.7-5.4%. However, the mortality rate after re-resection for recurrent disease can be as high as 25%4.

Presenting morbidities include the following:
Visual loss: Anterior extension to the optic chiasm can result in a classic bitemporal hemianopsia, unilateral temporal hemianopsia, papilledema, or unilateral/bilateral decrease in visual acuity. Children are frequently inattentive to visual loss, and formal testing may be required.
Endocrinologic derangement: This results from direct compression or destruction of the hypothalamus and pituitary stalk, leading to growth hormone deficiency (75%), thyroid-stimulating hormone deficiency (25-64%), adrenocorticotropic hormone deficiency (25-56%), and luteinizing hormone or follicle-stimulating hormone deficiency (40-44%). This can present as clinically significant short stature, hypothyroidism, and other signs of panhypopituitarism.
Diabetes insipidus: This is reported to occur in 9-38% of patients prior to surgery and in 76-94% of patients postoperatively.2

Race

No clear racial predilection has been reported.
Sex

The most recent large series demonstrate equal sex distribution, although a slight male preponderance has been historically reported.
Age

Peak incidence of childhood craniopharyngiomas occurs in individuals aged 5-14 years. Neonatal craniopharyngiomas are rare. Of the more than 300 cases per year in the United States, approximately one third involve children aged 0-14 years. The incidence of adult craniopharyngiomas has a second peak in individuals aged 50-74 years.
Clinical
History

Craniopharyngiomas produce symptoms by compression of adjacent neural structures. They can become quite large, obstructing cerebral spinal fluid (CSF) pathways (ie, third ventricle, Monro foramen) and causing hydrocephalus and increased intracranial pressure that leads to headaches, nausea, and projectile vomiting.

Symptoms at presentation may include the following:
Headache: Headaches occur in 60-80% of children with craniopharyngioma at presentation and are usually a symptom of increased intracranial pressure or hydrocephalus.
Vomiting: Classic projectile vomiting (frequently without nausea) accompanies headaches as a sign of increased intracranial pressure and is reported in 35-70% of children with these tumors at presentation.
Vision loss: As mentioned above (see Mortality/Morbidity), children are frequently unaware of significant vision loss; nevertheless, this symptom reportedly occurs in 20-60% of pediatric patients with craniopharyngioma at presentation. Classically, vision loss starts with a superior temporal field cut. However, the eccentric growth of these tumors can result in varying patterns and severity of vision loss, including decreased acuity, diplopia, blurred vision, and subjective visual field deficits.
The following symptoms related to endocrine dysfunction may be present:
Diencephalic syndrome: This term is used to describe emaciated hyperactive children who occasionally present with unusual eye movements and even blindness; these symptoms result from extrinsic compression of the hypothalamus. Conversely, damage to or invasion of the ventromedial hypothalamus can result in a dysregulation of energy balance and resultant obesity upon presentation.
Symptoms of growth hormone deficiency (ie, short stature): Growth hormone deficiency is the most common possible endocrinologic disturbance caused by craniopharyngiomas. One series reported that growth failure preceded the diagnosis at a mean of 4 years.
Symptoms of hypothyroidism
Weight gain
Lethargy
Fatigue
Cold intolerance
Dry skin
Dry brittle hair
Slow teething
Anorexia
Large tongue
Deep voice
Myxedema
Symptoms of adrenal insufficiency (ie, excessive thirst, frequent urination, fever): Secondary adrenal insufficiency is the second most common endocrinologic disturbance caused by craniopharyngiomas.
Symptoms of leuteinizing hormone/follicle-stimulating hormone deficiency: Gonadotropin deficiency is the most common presenting symptom of craniopharyngioma in adults. As many as 100% of presenting adolescents may have complaints of delayed puberty.
Mental status changes occur in as many as 25% of adults but are rare in children. Temporal lobe involvement can result in seizures, although this is rare.

Physical

Focus physical examination on the identification of neurologic and endocrine derangements.

Papilledema: Papilledema occurs in 25-40% of children and results from increased intracranial pressure.
Visual field deficits
Formal testing is generally required to identify visual field deficits in children, which likely explains the wide reported range (10-95%) of patients with craniopharyngioma.
Given the typical proximity of the tumor to the optic nerves, optic chiasm, and anterior optic tracts, the common discovery of visual fields defects at presentation is not surprising.
See-saw nystagmus: Although often referred to as a classic physical examination finding among children with parasellar tumors, the literature reports an incidence rate of less than 10%.
Cranial nerve palsy: With the notable exception of the optic nerves, cranial nerve palsies are relatively rare, with a reported incidence rate of 8% for children at time of diagnosis.
Endocrine effects
Short stature or growth retardation
Short stature or growth retardation is the most common endocrine derangement associated with this tumor.
Growth retardation (as documented on formal pediatric growth charts) is reported in 86% of patients with craniopharyngioma at presentation.
Obesity and weight gain
This is the third most common endocrine abnormality associated with craniopharyngiomas.
Hypothyroidism, growth hormone deficiency, and direct hypothalamic injury can contribute to obesity and weight gain.
Obesity and weight gain are reported in 20% of presenting patients.
Hypothyroidism: Hypothyroidism can manifest as weight gain, dry skin, brittle hair, and bradycardia.
Precocious or delayed puberty: Precocious or delayed puberty is the fourth most common endocrine derangement associated with craniopharyngiomas and is present at diagnosis in 10-15% of patients. This is the most common presenting sign in adolescents.
Intellectual or emotional disturbance and somnolence: These signs are most likely the result of either hydrocephalus or thyroid dysfunction.
Enlarging head circumference: This finding is highly suggestive of an intracranial mass or hydrocephalus, particularly when paired with papilledema.
Ataxia: This is another sign of increased intracranial pressure or hydrocephalus, which is present in 5-10% of patients at initial evaluation.
Seizures: These are rarely described as a presenting feature.
Focal motor weakness: This is also rarely described as a presenting feature.
Causes
No known environmental or infectious causes predispose to the development of craniopharyngiomas.
Little is also known regarding the genetic basis for craniopharyngiomas. Transformation of normal cells into neoplastic ones likely involves multiple genomic changes, including loss of tumor-suppressor genes, activation of oncogenes, and alterations in DNA repair and methylation mechanisms. Although these events have started to be elucidated for neuroepithelial neoplasms such as gliomas, little progress has been made in understanding these events in craniopharyngiomas. Some chromosomal abnormalities, including deletions, translocations, and increased copy numbers, have been recognized but are largely nonspecific.4 The significance of these findings remains to be determined.
Craniopharyngioma studies have identified the beta-catenin pathway as playing a potential role in the pathogenesis of these tumors.1 Beta-catenin is a downstream component of the Wnt signal transduction pathway that plays critical roles in the regulation of cellular proliferation, morphology, and development. One study showed that the accumulation of nuclear beta-catenin as measured immunohistochemically was able to help differentiate craniopharyngiomas from Rathke cleft cysts.6

Differential Diagnoses

Astrocytoma
Ependymoma
Neuroblastoma
Other Problems to Be Considered

Cerebral aneurysm
Meningioma
Oligodendroglioma
Optic pathway gliomas
Pineoblastoma
Pituitary adenoma
Primitive neuroectodermal tumor
Rathke cleft cyst
Workup
Laboratory Studies

The following laboratory measurements are indicated in patients with craniopharyngiomas:
Serum electrolytes levels
These routine tests establish readiness for surgery.
Importantly, the endocrine dysfunction frequently associated can cause abnormalities in several of these test findings.
Growth hormone levels, including thyroid-stimulating hormone/thyroid hormone levels, steroid hormone levels (cortisol), follicle-stimulating hormone/luteinizing hormone levels
Obtain these tests preoperatively as a baseline.
Obtain tests to allow for perioperative hormone replacement as necessary.
Imaging Studies
Skull radiography
Approximately 85% of craniopharyngiomas have calcifications above or within the pituitary fossa on plain radiographs of the skull.
Enlargement of the sella turcica can also be reliably identified.
If hydrocephalus is associated with a tumor in a young patient, split sutures may be observed.
Head CT scanning
This may be the only preoperative radiographic study needed because craniopharyngiomas are observed with mixed solid and cystic components, and the solid component is enhanced following the administration of intravenous contrast.
CT scanning is better than MRI at revealing the common tumor-associated calcifications.
Peritumoral edema is rare.
Hydrocephalus is identified and readily characterized.
Brain MRI
MRI is better than CT scan at determining the relationship of the tumor to adjacent normal structures.
As with CT scanning, mixed solid and cystic components are identifiable, and multiple cysts are common.
The solid component of the lesion frequently enhances following intravenous contrast administration, and a smooth ring of enhancement of the cyst wall can also be present.
Craniopharyngiomas are usually sharply demarcated and smoothly marginated.
Distortion or obliteration of the third ventricle is common.
Frequent involvement of the optic chiasm is found.
Obtaining postoperative imaging within 48 hours after surgery to best distinguish residual tumor from postsurgical changes is important.
Other Tests
Preoperative intellectual or psychological assessment may be useful as a baseline examination prior to undertaking curative therapies.
Procedures
Angiography: Cerebral angiography can be useful in planning the surgical approach, although it has been largely replaced by MRI/magnetic resonance angiography (MRA) in most centers. A vascular blush can be observed, although the tumor is not visible.
Histologic Findings
Craniopharyngiomas can be histologically classified into 3 types: adamantinomatous, papillary, and mixed. The adamantinomatous type is by far the most common in children (92-96%). Grossly, these tumors usually have both solid and cystic components. The fluid within the cysts has been historically described as "crankcase oil" because of its frequently dark and oily intraoperative appearance. Upon microscopic examination, the fluid contains abundant lipids with birefringent cholesterol crystals. Clinically, spillage of the cyst fluid into the subarachnoid space can cause severe chemical arachnoiditis.
Microscopic examination of the solid components reveals an epithelial tumor with angulated columnar cells resting on a collagen basement membrane. Papillary structures are common, and calcification is nearly universal. Large tumors may induce an intense glial reaction and intensely adhere to the underlying normal brain.
Staging
Preoperative and postoperative MRIs of the brain are adequate staging modalities for most children with craniopharyngioma. The postoperative scan is important in assessing residual disease. Neuraxis dissemination does not occur; thus, full spinal evaluation is unnecessary in an asymptomatic patient.

Treatment
Medical Care
Endocrine complications in patients with craniopharyngioma include the following:
Long-term hormone replacement is the primary medical treatment associated with childhood craniopharyngiomas and includes the administration of intranasal vasopressin (desmopressin acetate [DDAVP]), corticosteroids, thyroid hormones, growth hormones, and sex hormones.
Perioperative care includes attention to frequently associated multiple hormone deficiencies.
Frequently, perioperative corticosteroid administration (stress doses) is required.
Chemotherapy can be considered for progressive disease that is unresectable and for which radiation therapy has already been used or is contraindicated.
The use of chemotherapy in the treatment of craniopharyngioma is still under investigation. The use of systemic cytotoxic chemotherapy has not been shown to be of benefit in this disease.
Systemic use of interferon alpha has been attempted in a clinical trial. The rationale for use of this agent was based on the similar epithelial origin of craniopharyngiomas and squamous cell carcinomas, in which interferon alpha has shown some efficacy. In a phase II trial, Jakacki et al (2000) used interferon alpha at a dose of 8 million U/m2 administered subcutaneously every day for a 16-week induction period and then the same dose 3 times/wk for 32 additional weeks in 15 patients with recurrent or progressive craniopharyngioma.7 Although an objective radiographic response was seen in only 3 of 12 patients who were able to be evaluated, the time until radiation therapy was required was delayed in those patients. However, 60% experienced moderately severe toxicities (eg, hepatic, neurologic, cutaneous), but these were all reversible with discontinuation or dose reduction.
Another, more tested chemotherapeutic modality is intracavitary/intracystic bleomycin, an antibiotic that induces DNA strand breaks and acts as an antineoplastic agent. First reported in 1985, this therapy involves placement of an Ommaya-type catheter into the cyst cavity.8 After confirming no leakage from the cavity after dye instillation, administration of bleomycin can commence (eg, 5 mg every other day until a total cumulative dose of 30 mg). Takahashi et al (2005), reported regression of the cystic cavities in 10 of 11 patients, with minimal adverse effects.8 Intratumoral therapy has also been performed using interferon alfa, with similar results. Despite the relative safety of these approaches, long-term vascular abnormalities such as moyamoya and aneurysms have been identified in pediatric patients with craniopharyngioma, especially in those who received both radiation therapy and intracystic therapy.9
Intracavitary irradiation (brachytherapy) has also been attempted in patients with recurrent craniopharyngioma. The local radiation doses ranged from 200-267 Gy, and complete or partial cyst resolution was seen in 71-88% of cases. However, the appropriate isotope to use and whether intracavitary brachytherapy has any impact on overall outcome remains unclear.4
One report described the use of carmustine (BCNU)–impregnated wafers (Gliadel: Guilford Pharmaceuticals, Inc; Baltimore, Maryland) in a patient with recurrent craniopharyngioma.10
Given the morbidity of repeated surgeries for recurrent craniopharyngiomas after radiation therapy has failed, further research into other therapies for these locally invasive tumors is desperately needed.
Surgical Care

Treatment options include radical surgery, conservative surgery with postoperative radiotherapy, and palliative surgery. Although reports suggest management of craniopharyngiomas with limited surgery or conventional external-beam radiotherapy alone, these methods are not widely used. Newer management options such as stereotactic radiosurgery or radiotherapy are promising but remain largely experimental.

Radical surgery
Historically, initial management of craniopharyngiomas has been surgical. Unfortunately, true complete resection of these tumors is challenging, even for experienced neurosurgeons who operate on several children with craniopharyngiomas each year.
Frequently, these tumors densely adhere to the optic chiasm, pituitary stalk, and internal carotid artery and often invade the region of the third ventricle; therefore, not surprisingly, radical surgery frequently causes significant morbidity including panhypopituitarism, neurologic deficits (cranial nerve palsies, hemiparesis, aphasia), and visual field deficits or blindness.
The postoperative mortality rate currently ranges from 0-20%, with the most recent series reporting rates of approximately 5-10%.
Perhaps most disheartening, gross total resection does not prevent recurrence. Following radical resection, local relapses are described in 0-60% of patients.
One series reported that complete excision was achieved in only 63% of patients treated with radical surgery, and one half of the tumors believed to be completely excised subsequently recurred.11
Conservative surgery alone: Morbidity and mortality associated with radical surgery led neurosurgeons to attempt lesser resections; unfortunately, limited surgery alone resulted in worse local control (75-90% local progression is reported) and even greater morbidity because of the need for repeated resections for recurrences.
Conservative surgery with postoperative radiotherapy
Because limited surgery does not prevent recurrences and radical surgery carries unacceptable morbidity and mortality, postoperative external-beam radiotherapy has been added to limited surgery in an effort to improve local control.
The literature seems to support this approach, with a reported long-term control of approximately 80-95% at 5-20 years and a low risk of long-term morbidity.
Risk of parenchymal brain injury or second malignancy caused by radiation therapy is estimated to be less than 1-2%.
Some advocate postoperative radiation even after gross total resections, particularly if residual calcifications are noted on postoperative imaging studies (this carries a poor prognosis).
In general, radiotherapy is administered using field arrangements similar to those used for pituitary adenomas (>2 fields, narrow margin around gross tumor volume). A dose response for craniopharyngiomas has been reported; thus, the total tumor dose is generally 5000-5500 cGy in 25-30 fractions.
Children younger than 3 years may not be candidates for such radiotherapy because they can develop unusually severe long-term adverse effects.
Palliative surgery
Conservative management with limited surgery and external-beam radiotherapy requires close monitoring of the neurologic status during treatment.
During or soon after radiotherapy, craniopharyngiomas can undergo cystic degeneration, which can lead to obstruction of cerebrospinal fluid outflow or compression of the optic apparatus, with potentially devastating consequences.
Fortunately, early recognition and appropriate surgical treatment followed by conventional full-dose radiotherapy are associated with good long-term outcome.

Consultations
Obtain consultations from the following:
Pediatric neurosurgeon
Radiation oncologist
Pediatric endocrinologist
Pediatric hematologist or oncologist
Diet
Attention to special neurologic and endocrinologic concerns is prudent. Weight gain can be dramatic and a significant long-term problem. Nutritional consultation can be helpful.