21 Optic Pathway Glioma and Juvenile Pilocytic Astrocytoma

10.1055/b-0040-177077

21 Optic Pathway Glioma and Juvenile Pilocytic Astrocytoma

Neil Majmundar, John R.W. Kestle, Douglas L. Brockmeyer, Jean Anderson Eloy, and James K. Liu

Abstract

This chapter describes the prevalence, natural history, and management of optic pathway gliomas (OPGs) in the pediatric age group. The authors discuss the presentation of OPGs in both the general population and neurofibromatosis type 1 (NF1) patients. The various treatment modalities of observation, chemotherapy, radiation therapy, and surgery are discussed. The role of endoscopy for the treatment of these tumors is discussed, and two case examples are presented demonstrating the importance of multimodal therapy.

21.1 Introduction

Optic pathway gliomas (OPGs) are rare benign tumors that involve eloquent neurologic structures, such as the optic nerves, chiasm, tracts, radiations, and hypothalamus. This relatively rare tumor type accounts for approximately 2 to 7% of all pediatric brain tumors. ¹ ^, ² Approximately 60 to 65% of these tumors are diagnosed in children younger than 5 years of age and nearly 75% during the first decade of life. ¹ ^, ² Although they are typically found in a younger age group, with a mean age at presentation of 8 years, OPGs have been reported in patients up to the age of 79 years. ¹ ^, ³ In the general population, they tend to present proportionately in men and women. ¹

The prevalence of OPGs is greater in patients with neurofibromatosis type 1 (NF1) when compared to sporadic cases in the general population, affecting approximately 11 to 30% of children with NF1. ¹ ^, ⁴ More than half of all OPGs occur in patients with NF1. The diagnosis of NF1 has a large impact on the clinical presentation, natural history, and treatment paradigm in patients with OPGs. In these patients, OPGs generally have a more benign presentation and clinical course. They can also be bilateral, multifocal, and found within the optic nerves. ¹ They are not typically found at the hypothalamus in patients with NF1. However, when they do occur at the hypothalamus, they can exhibit an aggressive clinical course, presenting with diencephalic syndrome resulting in cachexia and hypersomnia. ¹ OPGs in patients with NF1 rarely progress after the patient reaches 6 years of age, significantly changing the manner in which this disease is treated when compared to patients with sporadic OPGs. ⁵ Although the pathologic and radiographic appearance of OPGs in patients both with and without NF1 may be similar, OPGs found in NF1 patients are noticeably less aggressive than sporadic cases in the general population. ⁶

Histologically, the majority of OPGs are comprised of WHO grade I juvenile pilocytic astrocytomas (JPAs), while a smaller proportion are pilomyxoid astrocytomas. In rare instances, they can be WHO grade II astrocytomas. JPAs are most commonly found in the cerebellum (60%), followed by the optic pathway (optic nerve/chiasm, hypothalamus/third ventricle; 25–35%), and finally the pons/medulla and tectum. ¹ Because of their intimate involvement with critical neurovascular structures, such as the optic pathway and hypothalamus, the optimal treatment remains controversial. In this chapter, we discuss the clinical presentation, natural history, and multimodal management of OPGs.

21.2 Natural History and Clinical Presentation

The true prevalence and natural progression of OPGs is difficult to determine, as many of these patients only present once they become symptomatic. The natural history can vary greatly among patients, as it can depend upon the presence of NF1, age of onset, and location of the tumor. Generally, OPGs are low-grade lesions with a slow growth rate and good long-term patient survival. ¹ However, their natural history can sometimes be unpredictable, with variable growth patterns ranging from extended periods of tumor stability to rapid progression, or they can have erratic growth patterns, with alternating periods of growth and stabilization. ⁷ Spontaneous regression of OPGs has also been reported in patients with close observation and serial imaging. ²

While a proportion of patients with OPGs may be asymptomatic, many patients with OPGs can present with a variety of symptoms depending upon size and location of the tumor. Most frequently, patients with OPGs present with decreased visual acuity. However, if the tumor involves the intraorbital optic nerve, patients may present with proptosis, strabismus, and vision loss due to pressure upon the orbital contents and optic nerve. ⁵ OPGs isolated to the optic nerve do not generally infiltrate the eye, but cause extrinsic compression of the globe. ⁸ Patients with intracranial tumors may present with visual symptoms, which can range from impaired color vision, decreased visual acuity, visual field deficits, optic atrophy, and total blindness. Intracranial tumors may also present with hypothalamic and endocrine disturbances, such as precocious puberty, anterior pituitary dysfunction, obesity, and diencephalic syndrome, due to the relative proximity of the hypothalamic–pituitary axis. When OPGs obstruct the normal flow of cerebrospinal fluid (CSF), patients can develop obstructive hydrocephalus, often requiring surgical intervention, such as CSF shunting and/or tumor debulking. ¹

OPGs can be located anywhere along the optic pathway, including the optic discs, nerves, chiasm, tracts, and radiations. Approximately 25% of OPGs occur at the optic disc and nerves, and 40 to 75% occur at the chiasm. ¹ About one-third to two-thirds of all chiasmatic OPGs can also involve the third ventricle or hypothalamus. ¹

The prognosis for OPGs varies with age and symptoms at presentation, preexisting diagnosis of NF1, and location. Typically, sporadic OPGs in children without NF1 are thought to be more aggressive and result in worse clinical outcomes. ⁸ In a recent series of 65 pediatric OPGs, the event-free survival rate at 4 years was higher in NF1 patients than in non-NF1 patients (72.9 vs. 48.4%, respectively), while the overall survival rate at 4 years was 90% for NF1 and 84.3% for non-NF1 patients. ⁷ When sporadic OPGs are diagnosed before the age of 5 years, a less favorable prognosis is expected. ¹ Anteriorly located OPGs within the optic pathways, in the presence of NF1, have a more favorable prognosis. Tumors can either present in a perineural or an intraneural growth pattern. Patients with NF1 tend to have a perineural growth pattern, while sporadic cases generally exhibit an intraneural growth pattern. Patients with OPGs confined to the optic nerve have a higher rate of survival than patients with OPGs involving the optic chiasm/hypothalamus. Although progression- or event-free survival varies in many case series based upon OPG location, age at presentation, and treatment modality, the 5-year event-free survival rate ranges from 30 to 40%. ⁹

Histologically, OPGs are low-grade gliomas that can manifest as pilocytic, fibrillary, or pilomyxoid astrocystomas. ¹ Pilocytic astrocytomas comprise the majority of OPGs and express a biphasic pattern with Rosenthal fibers and eosinophilic granular bodies. The more aggressive pilomyxoid astrocytomas display piloid cells in a loose fibrillary and myxoid background, and, unlike the pilocytic subtype, they do not have Rosenthal fibers and rarely demonstrate eosinophilic granular bodies. ¹ The pilomyxoid subtype also has a younger mean age at presentation (18 months), has a more aggressive clinical course, and is more likely to present with CSF dissemination. ¹

21.3 Management Options

The management of and treatment options for OPGs consist of observation with serial imaging, chemotherapy, radiotherapy, and surgery. An individualized tailored approach of management is recommended, with a multidisciplinary team of specialists consisting of neurosurgeons, neuro-ophthalmologists, neuro-oncologists, endocrinologists, radiation oncologists, and otolaryngologists.

21.3.1 Observation

Patients with small tumors that are confined to the optic nerves or chiasm with preserved visual function and non-obstructed CSF pathways can be carefully observed using a wait-and-scan strategy. As many as half of all OPGs have been reported to remain stable and require no intervention. ² Patients with NF1, who tend typically to have a more benign course, with fewer patients needing intervention for tumor progression, typically undergo observation initially with a serial wait-and-scan approach, especially in the presence of stable radiographic disease or stable visual/neurologic status. ¹ ^, ² NF1 patients should have close follow-up with a neuro-ophthalmologist and undergo a complete ophthalmologic examination every year until they reach 8 years of age, and then every 2 years afterward. ¹ ^, ⁸ The examination should include funduscopy, visual acuity, and visual field assessment. Spontaneous regression of OPGs has also been reported in patients with close observation and serial imaging. ² This excludes patients who develop visual symptoms, obstructive hydrocephalus, or endocrine dysfunction from involvement of the hypothalamic–pituitary axis.

Interventional treatment (chemotherapy, radiation therapy, and surgery) is indicated in patients who exhibit radiographic tumor progression or become symptomatic from increased intracranial pressure (mass effect or obstructive hydrocephalus), visual worsening, or diencephalic syndrome. Treatment is individualized with the goal of reducing tumor mass effect and volume while preserving neurological function.

21.3.2 Chemotherapy

Chemotherapy is generally considered the first-line treatment in symptomatic OPGs causing visual loss, hypothalamic–pituitary axis dysfunction, and endocrine disturbances. Chemotherapy is well tolerated in younger children and is associated with lower rates of complications and adverse long-term effects when compared to radiation therapy and surgery. Because radiation has an increased risk of long-term cognitive deficits and growth hormone deficiency, chemotherapy is considered the primary treatment modality in children younger than 5 years of age who present with visual deterioration (▶ Fig. 21.1). ¹ ^, ⁵ A variety of chemotherapeutic agents, including carboplatin, cisplatin, vincristine, vinblastine, actinomycin D, lomustine, thioguanine, procarbazine, etoposide, tamoxifen, and temozolomide, have been used as adjuvant or first-line chemotherapy treatment for OPGs. ¹ However, the most optimal and effective agents have yet to be defined. The most widely used chemotherapy regimen is carboplatin and vincristine in a 10-week induction phase. This is then followed by carboplatin/vincristine-maintenance for 48 weeks, resulting in a progression-free survival of 50% at 5 years. ¹ The combination of cisplatin and etoposide has also been shown to improve visual acuity. ¹⁰ Temozolomide, which has been shown to help stabilize progression, can be considered an option for patients in whom first-line therapy has failed. ¹ Other combinations, such as a five-drug regimen utilized by Petronio et al, and another similar four-drug regimen, have been shown as reasonable first- and second-line treatments, respectively. ¹¹ ^, ¹²

Fig. 21.1 This 19-month-old girl presented with failure to thrive and visual loss. **(a)** Sagittal and **(b)** coronal views of the initial postgadolinium T1-weighted MRI showed a large enhancing lesion in the suprasellar and third ventricular region. An endoscopic transventricular biopsy revealed a juvenile pilocytic astrocytoma. Chemotherapy was initiated and a follow-up MRI 3 months later showed decreased central enhancement but increased hydrocephalus: **(c)** sagittal and **(d)** coronal views. A ventriculoperitoneal shunt was placed and additional courses of chemotherapy were given. Follow-up MRI 1 year later showed significant shrinkage of the tumor: **(e)** sagittal and **(f)** coronal views. Two years after chemotherapy treatment, tumor growth progressed within the third ventricle with a trapped right lateral ventricle: **(g)** sagittal and **(h)** coronal views. Tumor debulking was performed via a right transcortical transventricular transforaminal approach. Residual tumor was left adherent to the walls of the hypothalamus and cerebrospinal fluid pathways were opened up without requirement of an additional shunt: **(i)** sagittal and **(j)** coronal views.

21.3.3 Radiation Therapy

While an effective treatment for OPGs, the role for radiation therapy as a first-line therapy has diminished over the years due to its significant long-term side effects, which include the development of neurocognitive deficits, secondary neoplasms, neuroendocrine deficits (especially growth hormone deficiency), and moyamoya syndrome. ² ^, ¹³ Therefore, radiation therapy is administered as adjuvant therapy rather than primary treatment for progression of disease after failure of other treatment modalities. Studies regarding radiation therapy have varied, with some demonstrating no benefit of radiation over surgery or observation, while others reporting good visual outcomes and tumor-free progression rates. ¹ More recently developed modalities of radiation therapy, mainly proton beam radiotherapy, stereotactic radiosurgery, and intensity-modulated radiation therapy (IMRT), have demonstrated better results in terms of 5-year survival rates, with less neurocognitive decline and endocrine disturbances. ¹ Currently, radiation therapy is generally avoided as first-line therapy in patients younger than 5 to 7 years. Radiation treatment is delayed as late as possible in order to avoid the devastating effects of neurocognitive deficits and growth hormone deficiency in children. ¹ ^, ² ^, ¹⁴ ^, ¹⁵