Radiation Treatments in the Management of Craniopharyngiomas

Introduction

Craniopharyngiomas are benign extra-axial epithelial tumors that arise from squamous epithelial remnants of Rathke pouch near the pituitary gland. These cells may extend from the nasopharynx to the tuber cinereum and may arise within the sphenoid bone, the sella, or the suprasellar region. Although craniopharyngiomas are rare overall, they are the most common suprasellar tumor in the pediatric age group, accounting for as many as 5% of all intracranial tumors and up to 10% of pediatric brain tumors. Its incidence has been estimated to be about 1.5 per million people per year ^, but may be considerably higher in specific ethnic groups, such as Japanese children (5.25 per million). Craniopharyngiomas have a bimodal age distribution, generally appearing in between the ages of five and nine in children and between the ages of 60 and 74 in adults. In general, patients with childhood-onset craniopharyngioma experience more frequent rates of long-term health conditions than patients with adult-onset craniopharyngioma, though rates of survival are comparable.

Despite being histologically benign, craniopharyngiomas can cause severe and often permanent damage to nearby hypothalamic, visual, and endocrine structures. The presentation of these tumors may include symptoms related to endocrine derangement of the hypothalamic–pituitary axis, with severity depending on location, size, and growth rate. Mass effect from the tumor may result in increased intracranial pressure presenting as headache, nausea, and vomiting. Cases with larger mass lesions may also present with hydrocephalus, seen more commonly in children than in adults, as a result of the obstruction of the cerebral aqueduct or the interventricular foramina. ^, Compression of the nearby optic apparatus typically results in visual impairment, such as chiasmal syndrome and papilledema. Endocrine disruption often manifests as amenorrhea, hypothyroidism, or diabetes insipidus. ^,

The structural composition of these tumors may include solid, cystic, mixed solid and cystic, or calcified components. Traditionally, craniopharyngiomas have been classified as adamantinomatous or papillary. More commonly observed in the pediatric population, the adamantinomatous type is multilobulated and multicystic, is characterized as having calcifications with mixed composition, and is associated with higher rates of recurrence, morbidity, and mortality than the papillary type. Cysts of adamantinomatous craniopharyngioma contain concentrated proinflammatory cytokines compared to other types of brain tumors or healthy tissue. Recent studies have shown that, unlike for the papillary type, expression of proteins such as annexin A2, survivin, MMP-9, or VEGF could serve as biomarkers for recurrence or progression of adamantinomatous craniopharyngioma and that calcifications may result from expression of proteins like calretinin or osteopontin. ^, In particular, aberrant membranous expression of β-catenin correlates with poor patient survival, and mutations in this protein are found in approximately 75% to 96% of adamantinomatous craniopharyngiomas. ^, On the other hand, papillary craniopharyngiomas typically occur in adults and are often solid and spherical in composition. Importantly, approximately 95% of papillary craniopharyngiomas have been shown to harbor the V600E mutation in the proto-oncogene BRAF, and therapeutically targeting this pathway with small molecule inhibitors can serve as a viable treatment option. For both subtypes, low protein expression of claudin-1 correlates with invasive growth.

Current treatment strategies include cystic drainage, intracavity chemotherapy, limited or gross total resection, and radiation therapy. Administration of interferon alpha can also help to slow disease progression or to delay surgical intervention or radiotherapy in pediatric patients. For both adults and children, treatment strategies are often combined into a patient-specific treatment plan based on tumor size, presence of hydrocephalus, degree of pituitary endocrinopathy, age of the patient at presentation, and relation of the tumor to the optic chiasm and third ventricle. If total excision can be safely performed with minimal risk to these structures, surgery remains the treatment of choice, as it allows rapid decompression, minimizes recurrence, and also provides a histological diagnosis. However, judgment of minimal risk is often unclear, as some favor subtotal resection coupled with adjunctive therapy to achieve similar outcomes. Although surgical approaches are often curative, they harbor a high treatment-related morbidity and mortality due to close proximity of the tumor to crucial neurovascular structures. It has also been shown that surgical defects impact and accentuate the radiation dose received by tissues, such that consideration of resulting anatomical changes should be calculated into the treatment planning. Recurrent craniopharyngiomas must be considered separately because a secondary surgery is associated with higher risk of complications and a lower cure rate. ^, In addition, stronger adherence of the tumor to the floor of the third ventricle has been shown to correlate with worse surgical outcomes, and classifying the adherence can help predict the risk of hypothalamic injury. More recently, stereotactic radiosurgery (SRS) techniques have become increasingly utilized as either a primary or secondary treatment option for craniopharyngioma patients.

Surgical Outcomes

Complete surgical resection is a primary objective and has curative potential. In a recent series by Shi et al., 284 patients, of whom 58 were children, were treated surgically, without adjunctive therapy, between 1996 and 2006. Total, subtotal, and partial removal of the tumors were achieved in 237 (83.5%), 34 (12.0%), and 13 (4.5%) patients, respectively. ^, Upon follow-up, 23 (14.1%) patients experienced recurrence 1.0 to 3.5 years after total resection, and 24 patients (64.9%) experienced recurrence after 0.25 to 1.5 years after subtotal or partial resection. In this series, the early mortality rate was 4.2% for all patients. In another 25-year retrospective study by Van Effenterre et al., 122 patients underwent either gross total (59%), subtotal (29%), or partial (12%) surgical resection. During the follow-up period, 29 total patients (24%) experienced one or more recurrences. The delay to recurrence was 1 to 180 months, with a mean of 42 months and a median of 12 months. Patients who underwent total, subtotal, or partial removal experienced 13%, 33%, and 69% recurrence, respectively. Radiotherapy was reserved only for cases of recurrence. The surgical mortality rate was 2.5%, and overall survival was 95% at 2 years, 91% at 5 years, and 83% at 10 years.

Comparison of surgical complications across different series offers a variable picture. Most of the large series have reported a total resection rate of 59% to 90%. ^, The 10-year recurrence-free survival rates have been reported as 74% to 81% for gross total resection, ^{, ,} 41% to 42% after partial removal, ^, and 83% to 90% after combined surgery and radiotherapy. ^, Surgical mortality rates vary between 1.1% and 4.2%. ^{, , ,} Pituitary dysfunction may occur in 50% to 100% of patients, the most common being diabetes insipidus. Visual deterioration may occur in up to 50% of patients undergoing gross total resection, though the presence of papilledema prior to surgical intervention has been shown to correlate positively with an improvement in visual acuity postsurgery. Gross total resection has also been shown to result in poorer neuroendocrine outcomes in adults. However, giving special care to avoid complications can help mitigate postsurgical complications, as evidenced in a recent study demonstrating that hypothalamus-sparing surgery can reduce the risk of obesity in children by almost two-fold, from 54% to 28%. As another example, surgeries that preserve the pituitary stalk also reduce the rates of early or persistent diabetes insipidus in children by three- or eight-fold, respectively. Finally, it is well documented that recurrent tumors are associated with significantly higher risk and poorer outcome, with overall mortality rates reported between 10.5% and 40.6%. ^,