Introduction
The incidence of brain tumors, particularly brain metastases, has been increasing in certain patient groups, and the average annual adjusted incidence rate has been estimated to be 24.71 per 100,000 population between 2015 and 2019. This is mainly due to advances in the diagnosis of primary central nervous system (CNS) tumors ( Table 8.1 ), and improved outcomes and survival from systemic malignancies. Malignant brain tumors are associated with poor survival outcomes and often lead to a decline in patients’ functional and performance status. Hence, timely diagnosis, management, and coordination of care are crucial, and it is important for physicians, particularly primary care providers and internists, to be familiar with their basic approach and management. This chapter will review brain metastases, which are the most common malignant brain tumors in adults, along with meningiomas and gliomas, with an emphasis on their clinical presentation, diagnosis, and basic oncological management. It will also review some of the most common medical and neurologic complications of brain tumors and their management.
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Central Nervous System Metastases
CNS metastases are the most common malignant CNS tumors, and are common among patients with advanced solid malignancies, leading to significant morbidity and mortality. The brain parenchyma is the most commonly involved site in the CNS. Leptomeningeal metastases (LM) refer to the tumor cell infiltration of the cerebrospinal fluid (CSF), and leptomeninges of the brain and spinal cord (i.e., the pia and arachnoid mater, the inner membranes of the meninges), whereas dural metastases refer to the infiltration of the dura mater, the outer membrane of the meninges, by tumor cells. Cancer may also metastasize to the spinal cord as intramedullary tumors, to the epidural spaces causing spinal cord compression, as well as to the nerve plexuses and even individual nerves.
The true incidence of brain metastases (BM) is challenging to determine due to lack of mandated reporting to local and federal registries and comprehensive epidemiology data. Also, screening for BM is only recommended by consensus guidelines for specific malignancies or stages of disease, including patients with small and non–small cell lung carcinoma, melanoma, testicular cancer, alveolar sarcoma, angiosarcoma, and left-sided cardiac sarcoma. The incidence ranges from 10% to 40% of patients with solid tumors, and the annual incidence is estimated to be 70,000 to 400,000 cases per year in the United States and has been increasing with better systemic therapies, improved survival, expanded use of surveillance imaging, and greater awareness among oncologists. The most common systemic malignancies to metastasize to the brain are lung cancer, breast cancer, and melanoma, which account for 67% to 80% of BM, whereas prostate cancer, head and neck cancer, non–melanoma skin cancer, esophageal cancer, and Hodgkin lymphoma rarely metastasize to the brain. Population data is limited, though recent studies shed light on the epidemiology of BM at the time of systemic cancer diagnosis (i.e., synchronous BM) using the National Cancer Institute (NCI) Surveillance, Epidemiology, and End Results (SEER) database. Cagney et al. estimate the overall annual incidence of synchronous brain metastasis at 23,598 patients per year in the United States, based on SEER data from 2010 to 2013. The incidence per tumor type for all stages of disease was highest in patients with small cell lung cancer, lung adenocarcinoma, and non–small cell lung cancer (NSCLC) not-otherwise specified, with a prevalence of synchronous brain metastasis of over 10%. Considering only patients with metastatic disease at the time of diagnosis, metastatic melanoma was the most likely to present with synchronous BM (28.2%), followed by lung adenocarcinoma, NSCLC not-otherwise specified, small cell lung cancer, squamous cell carcinoma of the lung, bronchioalveolar carcinoma, and renal cancer, all with a prevalence of over 10%. Analysis of SEER data by Kromer et al. revealed similar results.
As for LM, they are diagnosed in about 5% of patients with solid tumors and often identified concurrently with parenchymal and dural metastases. However, the incidence of undiagnosed or asymptomatic LM has been reported to be greater than 20% in autopsy series. Breast cancer, particularly of negative hormonal receptor and Her2 expression status, is the most common solid malignancy that causes LM, followed by lung cancer and melanoma.
Pathophysiology
Tumor cells often acquire epigenetic and proliferative changes, including the expansion of preexisting or development of new blood vessel networks, leading to vascular invasion and subsequent hematogenous spread to the brain. Other routes of tumor cell spread to the CNS include perineural invasion and anterograde or retrograde dissemination through the Schwann cells, which is often observed in head and neck squamous cell carcinoma, and intracranial retrograde dissemination from spinal tumors such as ependymoma. Once inside the brain, tumor cells interact with brain endothelia and adhere to the brain parenchyma via upregulation of particular cell surface proteins and growth factors, then secrete inflammatory cytokines, through interaction with the surrounding astrocytes, promoting cell motility, invasion, and survival. LM also develop through hematogenous spread to the arachnoid via the arterial circulation, particularly in hematological tumors, through endoneural or perineural and perivascular lymphatic spread from vertebral metastases or head and neck cancers, or direct spread from BM in close proximity to CSF spaces.
Clinical Presentation and Diagnosis
The clinical presentation of BM is quite variable. Headache is a common complaint, occurring in up to 50% of patients, though it is neither sensitive nor specific for the diagnosis. The classic headache is diffuse, mild at onset, occurring mainly in the recumbent position due to peritumoral edema and increased intracranial pressure (ICP). It begins when the patient awakens in the morning, disappears shortly after arising, and returns the following morning. The question of when to image those without the classic “brain tumor headache” or those with chronic headache is a difficult one for primary care providers, neurologists, and oncologists alike. The US Headache Consortium recommends consideration of neuroimaging to rule out a secondary cause of headaches for those patients with an abnormal neurological examination, those who develop consistent and progressive headaches at an older age, those with atypical headache features, or headaches that do not fit the strict definition of migraine or other primary headache disorder. Atypical features include rapidly increasing headache frequency, history of lack of coordination, history of localized neurological signs, such as localized sensory or motor symptoms, and history of headache causing awakening from sleep.
Seizures are another common symptom in patients with BM and can occur at any time of the disease course. Neuroimaging should be considered for all adults presenting with a first unprovoked seizure. Patients may also present with focal neurological symptoms (i.e., aphasia, weakness, sensory loss, visual disturbances, ataxia), which often have a subacute onset, secondary to direct invasion or compression of eloquent brain structures. Cognitive or behavioral impairment is likewise common and often develops with multifocal BM (i.e., involving multiple areas of the brain responsible of memory encoding, registration, and recall, as well as personality changes) or secondary to increased intracranial pressure (ICP) or delayed brain tissue injury from radiation.
Classically, LM present with signs and symptoms of increased intracranial ICP due to decreased CSF reabsorption at the arachnoid villi and poor CSF ventricular outflow leading to hydrocephalus, and/or focal neurologic deficits involving multiple sites within the neuroaxis. Clinical manifestations include headache that is also worse in the recumbent position, dizziness, cognitive changes, speech problems, signs of focal cortical or cerebellar dysfunction, incontinence, and gait disorders. Malignant invasion of the arachnoid mater can lead to multiple cranial neuropathies and radiculopathies. Cranial nerves VI, VII, and VIII are most affected, leading to binocular diplopia, facial weakness, and/or hearing impairment. Nonspecific symptoms like hiccups and bilateral tinnitus can also be observed and should raise the suspicion of LM, particularly if they occur concurrently with the former symptoms. Involvement or compression of the small vessels in the subarachnoid space can occasionally lead to ischemic infarcts. Seizures from meningeal and cortical irritation are rare.
The National Comprehensive Cancer Network (NCCN) guidelines for CNS cancers provide an algorithm for establishing the diagnosis of BM. Magnetic resonance imaging (MRI) of the brain with and without contrast is the gold standard for brain tumor imaging, though computerized tomography (CT) with and without contrast is a reasonable alternative for those that cannot undergo MRI. Imaging of the neuroaxis should be considered in all cancer patients who develop new neurologic symptoms, while screening for asymptomatic BM is only recommended in patients with cancers associated with high risk of BM, including small cell lung cancer, advanced NSCLC, and advanced melanoma. BM typically appear as well-demarcated, solid or ring-enhancing lesions located in the gray-white matter junction ( Fig. 8.1 ). They involve the cerebral hemispheres in 80%, whereas the cerebellum and the brainstem are affected in about 15% and 5%, respectively. BM from melanoma, choriocarcinoma, germ cell tumors, thyroid carcinoma, and renal cell carcinoma are more likely to be hemorrhagic. In patients with a known history of cancer and little concern for alternative diagnoses, neuroimaging alone may be sufficient to make the diagnosis of BM. In those without a prior diagnosis, CT imaging of the chest/abdomen/pelvis or whole-body positron emission tomography (PET-CT) may reveal other sites of involvement outside the CNS that may be biopsied or resected for tissue confirmation. In those without evidence of systemic malignancy (almost a third of patients), or those with concern for an alternative diagnosis based on neuroimaging, a stereotactic or open biopsy, or surgical resection of the brain mass is recommended to direct further care.
LM may manifest as diffuse opacification and thickening of the leptomeninges and enhancement along the cerebral surface, cranial nerves, and nerve roots, or as minute enhancing nodules particularly in the posterior fossa, basal cisterns of the brain, and cauda equina ( Fig. 8.2 ). However, brain and spine MRI can be normal despite symptoms, as it has a sensitivity of only 70%. CSF cytology is the gold standard for diagnosis, but poor sampling, inadequate sample volume (<10.5 mL), and inefficient handling may lead to false-negative results. Serial CSF sampling and collection of CSF at the site of symptoms (i.e., ventricular for cranial disease and lumbar for spinal disease) increase the diagnostic yield. CSF flow cytometry increases sensitivity to leptomeningeal spread of hematologic malignancies. Other CSF findings include elevated proteins and low glucose levels. Liquid biopsies utilizing assays that detect spinal fluid circulating tumor cells or cell-free DNA are being developed for clinical use; some studies suggest that these technologies may be more sensitive than CSF cytology.
Oncological Management
The management of BM requires a multidisciplinary approach and depends on the patient’s clinical and radiological status, and the type of the primary malignancy. Guidelines have been proposed by the Society for Neuro-Oncology (SNO), American Society of Clinical Oncology (ASCO), and American Society for Radiation Oncology (ASTRO). As most patients with BM have advanced systemic disease, the prognosis remains generally poor, with a median overall in the range of months in most patients. Diagnosis-specific graded prognostic assessment (DS-GPA) indices exist to help estimate survival in BM patients; they were developed by identifying major prognostic factors (performance status, age, presence of extracranial metastases), based on aggregated data of patients with BM across various tumor subtype cohorts. In general, management is aimed at palliation in patients with poor prognoses. More aggressive management is reserved for select patients with good prognoses (such as a young patient with excellent performance status and BM from hormone receptor/HER2-positive breast cancer with estimated median survival time of 25.3 months per GPA).
The role of surgery depends on the diagnostic need and extent of disease. Surgical resection may be necessary to establish a diagnosis in patients with no history of systemic malignancies or with multiple concurrent cancers. In patients with good functional status, controlled or absent systemic disease, and a single, surgically accessible brain metastasis, surgical resection may be indicated and associated with improved survival and lengthened functionally independent survival time. In those with multiple BM, surgical resection may be considered for the removal of a bulky, dominant lesion causing symptoms refractory to corticosteroids for palliation. In patients who develop hydrocephalus from diffuse LM, a ventriculoperitoneal shunt may be considered for CSF diversion. On the other hand, surgical resection can be deferred in patients with BM from radiosensitive tumors (i.e., small cell lung cancer, select germ cell tumors, hematological malignancies), or tumors with effective CNS-penetrant therapies, such as EGFR-mutant NSCLC and BRAF-mutant melanoma. Laser interstitial thermal therapy (LITT) is a less aggressive surgical approach, where tumor is ablated by laser-derived thermal energy emitted through a catheter. Although its established role is limited to radiation necrosis, it can be used to treat select recurrent BM.
Whole-brain radiotherapy (WBRT) is the historic standard for palliative radiotherapy in BM. It results in improvement in neurologic function, and decreased incidence of intracranial recurrence and neurologic death. However, WBRT is associated with increased neurotoxicity, particularly fatigue and neurocognitive dysfunction. Hippocampal avoidance WBRT (HA-WBRT) preserves the radiosensitive neural stem cells of the hippocampus and is associated with reduced decline in memory and improvement in quality of life compared to the standard WBRT in patients devoid of BM in close proximity to the hippocampi. The addition of memantine, an NMDA receptor antagonist, during the course of WBRT and up to 6 months afterward, has also led to prolonged time to cognitive decline.
The limitation of WBRT created an interest in studying treatment with more focused forms of radiotherapy, like stereotactic radiosurgery (SRS) or stereotactic radiotherapy (SRT), which consist of a single fraction of highly conformal, high-dose radiation (SRS), or multiple fractions of moderate doses of radiation (SRT). Multiple studies failed to identify a survival advantage to the combination of SRS and WBRT, or to WBRT, compared to SRS alone, despite improved local and distant brain recurrence rates. Thus, SRS alone is the preferred modality for patients with a limited number and small volume of BM, especially in older patients, and patients with progressive extracranial disease, as SRS is associated with less cognitive side effects and permits a more rapid transition to systemic therapies. Although SRS did not use to be an option in patients with more than 3 BM, more recent studies have shown comparable outcomes with SRS in patients up to 10 BM. WBRT is currently reserved for patients with numerous (>10) BM, or patients with diffuse symptomatic LM.
Historically, systemic therapies played little role in the direct treatment of BM, but rather for control of systemic disease. However, advances in immunotherapy and the development of targeted therapy agents that cross the blood-brain barrier have shifted this paradigm. In melanoma, the combination of the immune checkpoint inhibitors ipilimumab and nivolumab has been established as an efficient therapy of BM after significant CNS responses and clinical benefits and durable responses were observed in an open-label, phase 2 study. Results from the COMBI-MB trial of dabrafenib plus trametinib in BRAF V600 -mutant metastatic melanoma showed an intracranial response in up to 88% of patients. Although response occurred relatively quickly, there was limited benefit in progression-free survival. Hence, this combination is used in symptomatic patients with BRAF V600 -mutant melanoma BM in need of a rapidly efficacious treatment. Other examples include EGFR inhibitors and ALK targeting agents in NSCLC. Osimertinib, a third-generation EGFR inhibitor has led to CNS response in up to 91% of patients with BM and LM from EGFR-mutant NSCLC, which translated into prolonged progression-free and overall survivals. Multiple agents targeting Her2, such as trastuzumab, and Her2 tyrosine kinase inhibitors, such as lapatinib, neratinib, and tucatinib, have been studied, alone or in combination with chemotherapy, in Her2-positive metastatic breast cancer, with CNS responses reaching 66% with some agents.
Meningiomas
Meningiomas are the most common primary intracranial tumors in the United States, accounting for 39.7% of all primary CNS tumors according to 2015–19 data from the Central Brain Tumor Registry of the United States (CBTRUS). Around 35,000 new cases are diagnosed every year, and the estimated population prevalence is around 1 in every 100 adults aged 45 years or older. They are mostly benign, slow-growing neoplasms derived from the meningothelial cells of the arachnoid layer, although they can rarely occur within the ventricles or extracranial sites such as the lungs. Risk factors for their development include ionizing radiation and familial syndromes like neurofibromatosis type 2. The World Health Organization (WHO) classification scheme grades meningiomas as grade 1 to 3, based historically on mitotic rate and specific histological features. Grade 1 meningiomas, also called benign meningiomas, are the most common, accounting for 80% of all meningiomas, and carry a very favorable prognosis. On the other end of the spectrum, WHO grade 2 and 3 meningiomas are more aggressive and are associated with a 78% and 44% survival rate at 5 years, respectively. Specific molecular and genetic alterations have been recently identified to be associated with worse prognosis and higher risk of recurrence, even in low-grade meningiomas. Such alterations include CDKN2A/B loss, TERT promoter mutation, chromosome 1p loss, and loss of nuclear expression of H3K27me3. This has led to the inclusion of homozygous CDKN2A/B loss and TERT promoter mutation in allocating meningioma a grade 3, irrespective of the histological criteria of anaplasia.
Clinical Presentation and Diagnosis
Meningiomas may present with headaches, seizures, or focal neurological symptoms due to compression or invasion of adjacent structures. Oftentimes, they are incidentally found on neuroimaging. A radiographic diagnosis of meningioma can be suspected when there is evidence of a homogeneously enhancing, extra-axial, dural-based mass with a dural tail and CSF cleft ( figure 8.3 ). Calcifications, hyperostosis, and overlying skull remodeling are often present. Peritumoral edema, heterogeneous enhancement, and intratumoral necrosis may suggest a higher-grade meningioma (i.e., WHO grade 2 or 3). The main differential diagnosis of dural-based lesions includes dural metastases, CNS lymphoma, hemangiopericytoma, sarcoidosis, or other inflammatory or infectious processes such as tuberculosis. In cases of diagnostic uncertainty or concern for high-grade features, biopsy or resection can establish the diagnosis.
New PET modalities have been developed to detect the expression of somatostatin receptor, which is expressed in 70% of meningiomas, using somatostatin analogs 68 Ga-DOTATATE and 90 Y-DOTATOC. These have not been implemented in the standard practice yet but can help distinguish tumor from healthy brain tissue and postoperative changes in challenging cases.
Oncological Management
Meningioma management depends on the presence of symptoms, the histologic grade of surgically resected meningiomas, and, for high-grade meningiomas, the extent of resection. Most incidental meningiomas can be safely managed with observation and serial brain MRIs until persistent radiologic or clinical progression, given their often slow or absent growth. In symptomatic patients, including those with tumor-associated headache, focal neurological deficits or seizures, or in patients with rapidly growing tumors, surgery is indicated for both therapeutic and diagnostic purposes. The extent of resection is an important prognostic factor, and is defined by the Simpson grade that ranges from complete resection of the enhancing mass, with dural and bone resection, to biopsy alone. SRS is an alternative to surgery for small tumors in elderly or critically ill patients.
Patients with grade 1 meningiomas can be observed, without adjuvant treatment, even if a gross total resection, defined by no residual enhancement on postoperative MRI, has not been achieved. However, patients with grade 3 meningiomas, and those with partially resected grade 2 meningiomas require adjuvant radiotherapy, given the high risk of recurrence and high mortality rate.
Chemotherapy plays a limited role in the management of meningiomas, mostly as salvage therapy for refractory disease. Classical cytotoxic agents, including temozolomide, irinotecan, and hydroxyurea are not active. Recently identified promising agents include antiangiogenic compounds, such as bevacizumab and sunitinib, as vascular endothelial growth factor (VEGF) is often overexpressed in meningiomas. Somatostatin analogs and mTOR inhibitors have also been studied, given the strong and frequent expression of somatostatin receptors, and activation of the PI3K/AKT/mTOR pathway in meningiomas. However, all the listed agents have been evaluated in small patient cohorts, with varying outcomes, and are yet to be validated. Finally, pembrolizumab, an immune checkpoint inhibitor, has recently shown promising efficacy in recurrent high-grade meningiomas in a small phase 2 study, and various immune checkpoint inhibitors are currently explored in ongoing clinical trials.
Gliomas
Gliomas are the most common malignant tumors of the CNS and include astrocytomas, oligodendrogliomas, ependymomas, and a variety of rare histologies. Glioblastoma (GBM), a grade 4 glioma, is the most common and, unfortunately, the most aggressive subtype ( Fig. 8.4 ). GBM makes up 14.2% of all primary CNS tumors and 50.1% of all malignant CNS tumors, with an age-adjusted incidence in the United States of 3.22 per 100,000 persons. The second most common gliomas are astrocytomas and oligodendrogliomas. While the classification and grade determination were mainly based on histology, the 2021 WHO classification of CNS tumors categorizes gliomas mainly on molecular basis. Astrocytomas and oligodendrogliomas are characterized by a mutation in the isocitrate dehydrogenase (IDH) gene, in contrast to GBM where IDH is wild type. The only recognized risk factor for the development of gliomas is prior ionizing radiation exposure to the head and neck area, while a history of atopic disorders (i.e., allergies, asthma, eczema, hay fever) can be a protective factor.
Glioblastoma
Clinical Presentation and Diagnosis
As with BM and meningioma, GBM may present with headaches, seizures, or focal neurological symptoms. Due to the aggressive nature of the disease, symptoms may develop rapidly within the course of weeks. Brain MRI with and without contrast is the modality of choice for neuroimaging. The appearance can vary, but most often shows a supratentorial, heterogeneously enhancing mass with central necrosis and surrounding nonenhancing white matter signal that may be due to edema or infiltrating tumor ( Fig. 8.4 ). Hemorrhage, cystic changes, and multicentric enhancement are frequently present.
Diagnosis requires pathological confirmation, in the form of a biopsy or surgical resection. A hypercellular tumor with severe atypia, necrosis, and microvascular proliferation are hallmarks for a grade 4 glioma. In the absence of grade 4 pathologic features in an IDH wild-type astrocytoma, such as necrosis and microvascular proliferation, effort should be made to identify the presence of EGFR amplification, and/or TERT promoter mutation, and/or gain of chromosome 7 combined with loss of chromosome 10, which establishes the diagnosis of GBM.
O 6 -Methylguanine-DNA methyltransferase (MGMT) promoter methylation status is another important molecular marker in glioblastoma. The MGMT protein reverses alkylation of DNA, induced by alkylating chemotherapy agents, at guanine sites, and silencing of the MGMT promoter via DNA methylation results in its decreased expression. MGMT promoter methylation is reported in 30% to 40% of GBM and is associated with prolonged overall and progression-free survival, and better tumor response in patients treated with an alkylating agent.
Oncological Management
Management of GBM includes a combination of neurosurgery, radiotherapy, and chemotherapy. Referral to an experienced brain tumor neurosurgeon for maximum safe resection is imperative, as the extent of resection impacts survival. Gross total resection of the enhancing mass is associated with prolonged survival, and recent studies showed extended survival with a supramaximal resection including the enhancing mass and the surrounding nonenhancing disease. However, radical microsurgical resection is often limited by the invasive nature of the tumor and involvement of eloquent cortex. In the latter situation, a functional brain MRI can help optimize the surgical plan and achieve a maximal safe resection.
In 2005 Stupp et al. reported on the results of the European Organisation for Research and Treatment of Cancer (EORTC) and National Cancer Institute of Canada Clinical Trials Group (NCIC) trial and established the current standard of care for postoperative management of newly diagnosed glioblastoma. This consists of 6 weeks of focal irradiation (60 Gy divided into 2 Gy fractions per day, over the course of 6 weeks) with concurrent daily temozolomide, an alkylating agent, followed by six cycles of monthly adjuvant temozolomide. The regimen resulted in a median overall survival of 14.6 months, compared to 12.1 months for GBM patients treated with radiation alone. The 5-year analysis of the EORTC-NCIC trial confirmed that the greatest benefit of adding temozolomide was seen in those with MGMT promoter methylation. Although a prolonged (>6 cycles) treatment with adjuvant temozolomide has been suggested in patients with MGMT promoter methylated tumors, it has not been associated with improved progression-free or overall survival. No additional survival benefit has been reported with more frequent, daily dosing, of adjuvant temozolomide either. In select patients with MGMT promoter methylated GBM, the combination of temozolomide and lomustine, another alkylating agent, in the concurrent and adjuvant settings, was associated with improved overall survival compared to temozolomide alone in a randomized phase 3 trial. However, the sample size of patients was small in each treatment arm, and the effect was small in a univariate analysis.
Elderly patients usually have a worse prognosis and are less tolerant of radiation toxicity. A hypofractionated course of radiation (such as 34 Gy over 2 weeks, or 40 Gy over 3 weeks) can be considered and has shown to be noninferior to the standard 60 Gy radiation. Although no randomized study compares standard radiation plus temozolomide with hypofractionated radiation plus temozolomide, a phase 3, randomized study of patients 65 years and older with a newly diagnosed GBM and good performance status demonstrated increased survival with hypofractionated radiation plus temozolomide compared to hypofractionated radiation alone, especially in patients with MGMT promoter methylated tumors. For patients in whom combined chemoradiation may not be tolerated (due to comorbid conditions, poor functional status, patient preference, etc.), temozolomide monotherapy can be a reasonable treatment for those with MGMT promoter methylated tumors, whereas hypofractionated radiation therapy is a viable option for those with unmethylated tumors. This also applies to patients with immunosuppressive conditions.
Tumor treating fields (TTF) are also a standard-of-care option for glioblastoma. This modality consists of a portable device that provides low-intensity, intermediate-frequency, alternating electric field therapy, and disrupts mitoses selectively in dividing tumor cells. It is applied in the adjuvant setting, in addition to monthly temozolomide, and its daily application for more than 18 hours a day was associated with prolonged progression-free survival and overall survival compared to adjuvant temozolomide alone in a randomized clinical trial.
There is no standard of care for the treatment of recurrent glioblastoma. Options include neurosurgery for resectable recurrent disease, reirradiation (especially if the recurrence is distal from the original tumor), and/or systemic therapies such as temozolomide, lomustine, and bevacizumab. Bevacizumab is humanized VEGF antibody that is not associated with survival benefit but helps with improvement of peritumoral edema and control of related clinical symptoms. The combination of dabrafenib (BRAF inhibitor) and trametinib (MEK inhibitor) was associated with an overall response rate of 32% in patients with recurrent BRAF-mutant GBM in a phase 2, single-arm, study. Ongoing clinical trials are evaluating various targeted therapies, immunotherapies, newer chemotherapy agents, and other treatment modalities, and are encouraged by the NCCN guidelines.
Isocitrate Dehydrogenase–Mutant Gliomas
The IDH mutation was first incorporated in the classification of gliomas in the 2016 WHO classification of CNS tumors, and additional molecular alterations were identified to define the type and grade of IDH-mutant gliomas in the 2021 WHO classification of CNS tumors. The majority of IDH-mutant gliomas harbor a heterozygous point mutation in the IDH1 gene consisting of arginine-to-histidine substitution at codon 132 (R132H), although other point mutations in the IDH1 and IDH2 genes have also been reported. The presence of concomitant codeletion of the short arm of chromosome 1 and long arm of chromosome 19 (1p/19q codel), resulting from an unbalanced translocation between the two chromosomes, is required for the diagnosis of oligodendrogliomas, whereas astrocytomas lack the 1p/19q codeletion. Oligodendrogliomas are classified into WHO grade 2 and 3, the latter consisting of higher rates of cellular proliferation, vascular proliferation, and necrosis. Astrocytomas in adults can be of WHO grade 2, 3, or 4—a grade 3 tumor is histologically distinguished from grade 2 by increased cellular proliferation and pleomorphia, whereas a grade 4 tumor has the histological features of GBM. In addition, a homozygous deletion of CDKN2A/B gene automatically upgrades the tumor to an astrocytoma, IDH-mutant, WHO grade 4, as such deletion has been associated with significantly worse outcomes.
Besides prior exposure to ionizing radiation, risk factors for the development of IDH-mutant gliomas are poorly understood. IDH-mutant constitute about 4.4% among all CNS tumors, with an incidence rate of 0.25 per 100,000 for oligodendrogliomas, and 0.44 per 100,000 population for astrocytomas.
Clinical Presentation and Diagnosis
Most patients, particularly those with oligodendrogliomas, present with focal seizures, while about 30% of patients present with focal motor or sensory deficits. Given the slow-growing nature of these tumors, symptoms develop over the course of months before a diagnosis is established. On brain MRI, IDH-mutant gliomas appear as expansile, T2/fluid-attenuated inversion recovery (FLAIR) hyperintense lesions commonly located in the frontal lobes. Enhancement is rarely seen with grade 2 tumors, whereas grade 3 and 4 tumors can be partially enhancing. Cortical involvement and the presence of calcifications on susceptibility-weighted images (SWI) sequences are more characteristic of oligodendrogliomas. On the other hand, a T2/FLAIR mismatch sign, where a homogenous hyperintense signal on T2 sequence is countered with suppression of FLAIR signal in the lesion core compared to the rim, is highly specific for astrocytomas ( Fig. 8.5 ).
