Low-grade infiltrating gliomas are defined as World Health Organization (WHO) grade II primary brain neoplasms, and include astrocytomas and oligodendrogliomas. Accounting for approximately 15% of all gliomas and 5% of all primary brain tumors, they present most commonly in the second to fourth decade of life, with peak incidence occurring between 35 and 44 years of age. Presenting symptoms vary depending upon the neuroanatomic location of the tumor; seizures can occur in up to 80% of patients, as well as headaches, focal deficits, cognitive changes, and behavior changes. However, patients are often asymptomatic, and these brain lesions may be found incidentally.
Low-grade gliomas are slow-growing tumors associated with a median survival time ranging from 4 to 13 years, depending on the subtype; in almost all cases, the tumors undergo malignant transformation, ultimately leading to death.[4,5] Treatment consists of surgery, radiation therapy (RT), and chemotherapy. Given the relatively long disease course, the optimal management approach is a matter of debate. The uniform goal has been to prolong overall survival (OS), by delaying malignant transformation; and to maintain a good quality of life, by minimizing treatment-related sequelae. Treatment decisions for patients with low-grade gliomas are based on histologic and molecular characterizations of the tumors and the presence or absence of specific risk factors.
Low-grade gliomas are a heterogeneous group of tumors with differing morphologic characteristics. Recent advances in genomic analysis have led to the identification of molecular markers that play an important role in the classification, prognostication, and management of low-grade gliomas. Astrocytomas and oligodendrogliomas are the two primary histologic subtypes of low-grade glioma. The term “oligoastrocytoma,” an entity previously described based on histologic characterization, has been phased out in the 2016 WHO classification system, which uses both histologic and molecular information to define gliomas.
IDH1 and IDH2 are the most commonly mutated genes in low-grade gliomas, with mutations estimated to occur in > 70% of cases. IDH mutations are considered an early driver of glioma pathogenesis but are associated with better treatment outcome, since IDH-mutated tumors are more susceptible to chemotherapy. Other molecular markers are used to differentiate between oligodendrogliomas and astrocytomas. A combined loss of chromosomal arms 1p and 19q (1p/19q codeletion) is seen almost exclusively in oligodendrogliomas and is now pathognomonic for this malignancy. Mutations in CIC and FUBP1 also occur primarily in oligodendrogliomas, and their loss of expression is potentially associated with earlier recurrence and poorer outcome.[9,10] Low-grade astrocytomas commonly demonstrate a mutation in TP53 or inactivation of ATRX, both of which rarely occur in oligodendrogliomas.
A landmark study by The Cancer Genome Atlas (TCGA) Research Network, using comprehensive genomic analysis of low-grade gliomas, revealed different molecular subtypes of low-grade glioma, with distinct prognoses based on IDH mutational status and 1p/19q codeletion status. Patients with low-grade gliomas whose tumors had IDH mutation and 1p/19q codeletion (oligodendroglioma) had the most favorable prognosis, with a median survival time of 8 years; in contrast, patients with IDH mutation without 1p/19q codeletion (astrocytoma) had a median survival time of 6.4 years. Comparatively, patients with IDH wild-type low-grade gliomas had a markedly worse median survival time of 1.7 years, similar to the 1.1-year median survival time of glioblastoma patients with wild-type IDH.
Surgical resection is the primary modality of treatment for low-grade gliomas. Historically, the timing of surgery (early vs delayed) was a matter of debate, with early surgery offered to symptomatic patients and a watch-and-wait approach employed for patients with incidentally found tumors. However, retrospective evidence has demonstrated improved outcomes in patients who undergo early resection. Use of tissue samples obtained by resection enables a more accurate diagnosis than needle biopsy alone, which is associated with a relatively high rate of misdiagnosis. In addition to data showing that early surgery improved patient outcomes, there is evidence that an increased extent of resection leads to better progression-free survival (PFS) and OS.[15,16] In a retrospective volumetric analysis of extent of resection in low-grade gliomas, Smith et al found that patients who underwent > 90% extent of resection had a 5-year OS rate of 97%, compared with a rate of 76% in patients who had < 90% extent of resection. Intraoperative electrostimulation mapping during an awake craniotomy, for patients with tumors in eloquent areas of the brain, has demonstrated improved clinical outcomes, since it allows for more extensive resection while minimizing neurologic injury (Figure 1).[18,19] Thus, the appropriate initial management of low-grade gliomas is early maximum safe resection rather than watchful waiting. Figure 2 illustrates a management algorithm for patients with low-grade gliomas.
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