C H A P T E R Low-Grade Gliomas 26 Paul D. Brown, Michael D. Chan, Edward G. Shaw, and Martin J. van den Bent EPIDEMIOLOGIC AND ETIOLOGIC FINDINGS PRIMARY THERAPY The estimated annual incidence of low-grade gliomas in the Maximum surgical resection is associated with a more favor- United States is 2000 cases. Etiologic factors are unknown. able outcome. These tumors are seen with increased frequency in patients In pediatric low-grade gliomas, observation is recom- with types 1 and 2 neurofibromatosis. mended after gross total resection. After subtotal resection or biopsy, treatment (radiation therapy, chemotherapy) is usually PATHOLOGIC FINDINGS deferred until symptomatic or imaging progression. The most common pathologic types include pilocytic astrocy- In adults, after gross total resection of a pilocytic astrocy- toma (World Health Organization [WHO] grade I), diffuse toma, observation is recommended. After gross total or subto- fibrillary astrocytoma, oligoastrocytoma, and oligodendrogli- tal resection (or biopsy) of a low-grade glioma, irradiation oma (WHO grade II). may be given postoperatively or deferred until progression occurs. BIOLOGIC CHARACTERISTICS The recommended radiotherapy (RT) dose is 45 Gy to Combined 1p and 19q deletions are associated with a superior 54 Gy in 25 fractions to 30 fractions, treating the MRI-defined outcome and are most common in oligodendrogliomas. TP53 tumor volume with a 2-cm margin. mutations are more common in diffuse astrocytomas and are Early results from one large randomized clinical trial mutually exclusive from 1p/19q co-deletions. IDH1 mutations suggest disease and outcomes are similar for either temozolo- occur in the vast majority of low-grade gliomas and are found mide or RT for 1p/19q-deleted tumors although RT may have both in tumors with TP53 mutations and in tumors with a superior PFS for 1p-intact tumors; however, the period of 1p/19q codeletions. follow-up in this trial is immature and not yet adequate to make definitive treatment recommendations. CLINICAL MANIFESTATIONS AND Long-term follow-up of a large randomized clinical trial of PATIENT EVALUATION 251 patients with less than gross total tumor resection or older The mean age at presentation is 37 years. Most patients do not than 40 found significantly better PFS and overall survival have any signs of their disease (i.e., they are neurologically (OS) for those treated with RT followed by procarbazine, “intact”). The most common symptom is seizure. CCNU, and vincristine (PCV) compared to those treated with Age is the most powerful clinical prognostic factor for RT alone (RTOG 98-02). These results confirm a benefit for RT survival. Children have a significantly better outcome than followed by chemotherapy for select low-grade glioma adults. Other prognostic factors associated with better overall populations. or progression-free survival (PFS) rates include oligodendro- glioma histology, normal mental status, and smaller tumor RECURRENT DISEASE size. Several challenges constrain recommendations in this setting. The imaging features vary by pathologic type. Pilocytic It is difficult to differentiate recurrence from radionecrosis by astrocytomas are well circumscribed and contrast enhancing. clinical symptoms or signs alone or by conventional MRI or Diffuse fibrillary astrocytomas are poorly circumscribed and positron emission tomography (PET). Further, at recurrence, typically nonenhancing, best seen on a T2-weighted or fluid consideration must be given to the possibility that these attenuated inversion recovery (FLAIR) magnetic resonance tumors could have transformed to malignant gliomas, which imaging (MRI) scan. are treated differently. Low-grade gliomas are a pathologically and clinically diverse is best determined by weighing all prognostic factors, favoring group of uncommon central nervous system (CNS) tumors that “early” (or postoperative) irradiation for high-risk patients and occur primarily in children and young adults. The prognosis is delaying irradiation for lower-risk patients. The importance of principally affected by patient age and pathologic type of chemotherapy in the treatment of low-grade glioma is growing tumor. Studies assessing proliferation and molecular genetics based on a number of clinical trials.1 may provide additional insight into prognostic groups that are In this chapter, a comprehensive overview of low-grade at higher risk for developing recurrence and therefore may glioma is provided with an emphasis on adults. Topics covered benefit from adjunctive treatments such as radiation therapy include epidemiology, etiology, pathology, biology, clinical and chemotherapy. In general, more extensive resection is asso- manifestations, patient evaluation, management (including ciated with better prognosis. The optimal timing of irradiation surgery, radiation therapy, and chemotherapy), and toxicity. 452 CHAPTER 26 l Low-Grade Gliomas 453 EPIDEMIOLOGY AND ETIOLOGY Grading Systems Annually in the United States, it is estimated that 23,130 CNS The concept of dividing astrocytomas into discrete grades asso- tumors will be diagnosed,2 of which approximately 20,000 will ciated with a distinct clinical prognosis dates back to the mid- arise in the brain.3 Of these, approximately 2000 will be low- 1920s and early 1930s to the work of Bailey and Cushing, who grade gliomas.4 recognized a subset of astrocytomas that had a more favorable Etiologic factors for low-grade gliomas are largely outcome than glioblastoma.10 There have been many grading unknown. Low-grade astrocytomas have been associated with systems (e.g., Kernohan, St. Anne-Mayo, and Ringertz systems) von Recklinghausen disease (type 1 neurofibromatosis) and in the past, which assess nuclear abnormalities, mitoses, endo- type 2 neurofibromatosis.3 In addition, a direct link has been thelial proliferation, and necrosis. Currently, the most widely made between subependymal giant cell astrocytoma, an used and accepted grading system is the WHO system.7 WHO uncommon pathologic type of low-grade astrocytoma, and grade I lesions are well circumscribed and have low prolifera- tuberous sclerosis.5 tive potential, with the possibility of cure following surgery alone. Grade II neoplasms are infiltrative, as a rule recur, and tend to progress to higher grades of malignancy (e.g., grade II PATHOLOGY astrocytoma transforms to grade III anaplastic astrocytoma) Pathologic Classification despite initial low-level proliferative activity. All histopatho- logical grading schemes are limited by their need to separate Historically, low-grade gliomas have been considered a homo- gliomas artificially into three or four groups, when in actuality geneous group of neoplasms associated with a more favorable they exist along a biologic continuum and the diagnoses are natural history.6 In reality, they are a diverse group of tumors subject to considerable interobserver variation.11 For the found throughout the CNS, the outcome of which depends on present, this somewhat outdated method is still used in both a number of anatomic, pathologic, biologic, host, and treat- therapeutic decision making and prognostication, but it is fully ment factors. anticipated that in the near future reiterations of the WHO Table 26-1 summarizes the current World Health Organiza- grading system will incorporate imaging and genetic testing. tion (WHO) classification of primary CNS tumors as it applies to low-grade gliomas.7 Grade I tumors must be separated from grade II tumors because they have a different molecular back- BIOLOGIC CHARACTERISTICS AND ground. These tumors are well circumscribed, are considered MOLECULAR BIOLOGY benign, and if completely resected, they are typically cured. The pilocytic astrocytomas, which comprise nearly all of the Since the 1990s, our understanding of the biology of low-grade grade I cerebral astrocytomas, tend to be better circumscribed gliomas has increased. This has included studies of tumor and rarely transform.8 Although pilocytic astrocytomas occur proliferation, and both cytogenetic and molecular genetic more commonly in the cerebellum of children (juvenile pilo- studies. cytic astrocytoma), they also occur in the cerebral hemispheres and in particular near the optic pathway. Studies of Proliferation The diffusely infiltrative low-grade astrocytomas (WHO grade II) are the most common and include astrocytoma, Tumor proliferation can be assessed with Ki-67 labeling. A oligodendroglioma, and mixed oligoastrocytoma.7 Grade II large review on Ki-67 labeling revealed increasing values of gliomas are diffusely infiltrating tumors and are capable of Ki-67/MIB-1 labeling index with increasing grade of malig- undergoing anaplastic transformation with an incidence as nancy.12 The MIB-1 labeling index differentiates diffuse astro- high as 80%.8,9 Remaining are the uncommon low-grade cytomas (WHO grade II) from anaplastic astrocytomas (WHO glioma variants, including the pleomorphic xanthoastrocyto- grade III) and glioblastoma (GM) tumors. Similar findings mas, subependymal giant cell astrocytomas, and others, which have been reported in oligodendrogliomas.13 Although the are briefly discussed later in the chapter. MIB-1 labeling index is a clear prognostic factor in low-grade glioma, the absence of agreed-on low versus high cut-off values and interobserver variation between various institu- tions prevents its routine use. TABLE 26-1 Low-Grade Gliomas* Included in World Health Organization (WHO) Classification Genetic and Other Molecular Studies of Gliomas About 50%