A range of central nervous system tumors is reviewed in this article. Although substantial diversity exists among these tumors, unifying themes can be observed. The tumors discussed in this article are typically less invasive and follow a less aggressive natural history when compared with other brain tumors in this issue of Continuum, lending them the categorization of nonmalignant. However, the term nonmalignant is a misnomer. Many of these tumors can be associated with substantial morbidity and mortality. Their management can involve clinical and radiographic follow-up but often requires multimodality treatment including surgery, radiation, and systemic therapies. Substantial advances have been made in our understanding of the biology of these tumors, and these advances are beginning to influence therapeutic management. It is hoped that these advances will revolutionize the clinical care of patients with these types of brain tumors, leading to overall improvements in survival and quality of life.
The review begins with the most common primary central nervous system (CNS) neoplasm, meningioma. It then proceeds to another common CNS tumor, pituitary adenoma, and then on to less common tumors, such as craniopharyngiomas and glioneuronal tumors. A unifying feature is the recent discoveries and descriptions of specific, potentially targetable, driver mutations or fusions detected in these tumors.
In this section, the most common primary brain tumor, meningioma, is discussed.
Meningiomas have the highest incidence of any primary CNS tumor. Because many of these tumors are frequently diagnosed by imaging alone, the true incidence is likely much higher than that reported by the Central Brain Tumor Registry of the United States, which requires pathologic verification. With slow growth and a prolonged natural history, the prevalence of these tumors is likely the highest among the CNS neoplasms. The annual number of meningiomas diagnosed in the United States is 29,183, comprising 37.2% of all histologically diagnosed CNS tumors. Increasing age is the factor most closely related to meningioma incidence. These tumors are exceedingly rare in the pediatric population and become relatively common in older adults with a median age at diagnosis of 65 years. It is likely that the rate reported in older adults may be an underestimate because many older patients do not undergo resection and are often managed noninvasively. The slightly lower incidence in rural compared with urban environments may reflect a similar rate of underdiagnosis in some populations. Female sex is associated with a higher incidence with a ratio of 2.27 to 1. Lifetime exposure to estrogen or progesterone may increase the risk of meningioma development as may an elevated BMI.
The incidence of meningiomas in those who are Black is slightly higher than in those who are White. The majority of histologically diagnosed meningiomas are World Health Organization (WHO) grade I (80.6%), with the remainder grade II (17.6%) and III (1.7%). Taking into account that many radiographically diagnosed tumors do not undergo resection because of their small size, lack of clinical symptomatology, and relatively indolent natural history, the percentage of grade I meningiomas comprising this class of tumors is presumably higher.
Meningiomas are a frequent component of autosomal dominant neurofibromatosis type 2 (NF2), a familial neurocutaneous syndrome. For more information about this and other familial nervous system tumor syndromes, refer to the article “Familial Nervous System Tumor Syndromes” by Roy E. Strowd III, MD, MEd, MS, and Scott R. Plotkin, MD, PhD in this issue of Continuum. Approximately half of individuals with NF2 develop intracranial meningiomas, and many of them have multiple tumors. A smaller percentage (20%) develop spinal meningiomas. The age at diagnosis of meningioma is typically younger in patients with NF2 when compared with patients without NF2. Other inherited syndromes associated with an increased incidence of meningiomas include those associated with germline mutations of SMARCB1 (schwannomatosis), SMARCE1 (Coffin-Siris syndrome), and SUFU or PTCH1 (Gorlin syndrome, basal cell nevus syndrome, nevoid basal cell carcinoma syndrome).
Ionizing radiation is also a risk factor for meningiomas. The excess relative risk of developing meningioma after cranial radiation ranges across studies from 0.64 to 5.1. It is uncertain what effect the overall dose of radiation has on this risk. While results from studies vary, exposure to very-low-dose radiation via dental x-rays has not definitively been shown to increase the risk of meningiomas. Pediatric patients who have received radiation therapy to the brain as part of their treatments for childhood cancers (including CNS cancers) are at increased risk of developing meningiomas. In one study, one of eight survivors of childhood cancer who received cranial radiation developed meningioma by the age of 40. The interval between initial radiation exposure and diagnosis of radiation-induced meningioma is long, in the range of 2 decades; however, substantial variability exists. Shorter intervals appear associated with higher grades, although this may be impacted, at least in part, by publication bias. A true understanding is incomplete as it is only recently that molecular alterations associated with a radiation-induced meningioma have been described.
Meningiomas are thought to arise from the arachnoid cells of the inner surface of the dura mater. These cells are of neuroectodermal origin, specifically of the neural crest. Histologic analysis had long been the sole method of diagnosing and categorizing meningiomas. This is now being complemented by molecular studies demonstrating specific mutations, fusions, and methylation profiles that improve diagnostic certainty, inform prognosis, and illuminate potential therapeutic targets. It is predicted that the importance of these molecular features will grow and potentially supplant the histologic features.
The WHO grading system recognizes three different grades of meningioma: grade I (the most common and indolent form of meningioma), grade II (atypical meningioma, associated with increased risk of recurrence), and grade III (malignant meningioma, characterized by aggressive behavior and propensity to metastasize). Histologically, a variety of subtypes are described (table 3-1). These descriptors have limited clinical relevance. However, a few histologic subtypes are associated with a more aggressive natural history: clear cell and chordoid subtypes confer grade II or atypical status; rhabdoid and papillary subtypes confer grade III or malignant status. These subtypes usually exhibit other characteristics suggestive of a more aggressive natural history such as brain invasion, increased mitotic activity, and peritumoral swelling.
Molecular characteristics can also be used to subclassify meningiomas. Two distinct approaches can be used, and they may complement each other. The first is the evaluation of the tumor, most often via next-generation sequencing to screen for specific mutations or fusions. The second is to perform analyses of the methylation profile of the tumor genome. Approximately half of meningiomas harbor a mutation or exhibit loss of the NF2 gene that encodes the cytoskeletal protein merlin. In the small subset of radiation-induced meningiomas, approximately half have been shown to have NF2 fusions. Other frequently encountered mutations are found in NF2 nonmutated (wildtype) tumors. These include SMO mutations, which are found predominantly in tumors of the olfactory groove, and AKT1 or MTOR mutations found in tumors of the skull base. The close ties between molecular characteristics and neuroanatomic location raise the potential for empiric systemic treatments if efficacious agents are established in the future. The second approach using methylation profiling has been shown to be prognostic but not predictive of response to a specific therapy. The methylation profile appears to be a superior predictor of the risk of tumor recurrence when compared with histologic grade. This technique is not yet being used in routine clinical practice, but it may have future value in determining postoperative management for patients.
The search for and study of stemlike cells of origin for meningiomas is an area of growing interest. This area of research could open up additional potential therapeutic targets.
Patients with meningioma will present with symptomatology related to the neuroanatomic location of the tumor or asymptomatically with a tumor noted incidentally on imaging performed for an unrelated reason. As the tumors are most often extraaxial, symptoms are related primarily to pressure on the underlying nervous system tissue, although frank infiltration of the underlying tissue is observed in a subset of tumors. In most cases, because of the relatively slow growth rate of the tumor, the onset of symptoms is subacute. On average, meningiomas grow by approximately 0.24 cm per year when assessed by planimetric measurements, although it appears that the volumetric growth rate may be slightly higher. Some patients, however, will experience symptoms related to an overall increase in intracranial pressure. This may be the case if the growth of the tumor is rapid or if either CSF or venous outflow pathways are obstructed or impeded. The symptoms of increased intracranial pressure include headaches that are worse with the Valsalva maneuver or when lying down or are associated with nausea, vomiting, diplopia, and somnolence alone or in combination.
CNS imaging, either CT or preferably MRI, will often reveal a homogeneously enhancing lesion arising from the dura (case 3-1). Most meningiomas are intracranial (approximately 80%); however, meningiomas can occur in the spine (approximately 4%), as well. Approximately 15% of meningiomas do not have an anatomic site reported in the Central Brain Tumor Registry of the United States. The incidence of spinal meningiomas is higher in patients with NF2 compared with patients without NF2. In rare instances, meningiomas may metastasize outside of the CNS. The incidence of this is very low and extra-CNS staging is not a component of the routine care of patients with meningioma. Radiographic features that are suggestive of a potentially higher grade (II or III) of tumor and a more aggressive course include the presence of tumor necrosis, peritumoral edema, and location along the falx cerebri and convexity. These types of findings are indicative of a need to strongly consider resection for both diagnostic and therapeutic purposes.
A 52-year-old, otherwise healthy, right-handed woman presented with a focal motor seizure in her right arm, neck, and face. A few weeks before the episode, the patient noted decreased dexterity in her right hand.
Following the seizure, the patient was evaluated, and examination showed mild right upper extremity weakness, and MRI of the brain with contrast showed a homogeneously enhancing dural-based mass (figures 3-1a and 3-1b, coronal and axial sections, respectively). A moderate amount of surrounding edema was noted on the fluid-attenuated inversion recovery (FLAIR) sequence (figure 3-1c). A radiographic diagnosis of meningioma was made.
Given the size of the lesion as well as tumor-related epilepsy, the patient was referred for surgery. She underwent gross total resection of the tumor, and pathology was atypical meningioma (World Health Organization grade II). She received postoperative, fractionated radiation therapy to 60 Gy using an involved field approach.
This case exemplifies a common scenario with the diagnosis of meningioma: a middle-aged woman presenting with a symptomatic, dural-based enhancing lesion. The peritumoral edema was an unusual feature of the case. This degree of brain swelling can be observed with meningiomas of higher grade (II and III) and occasionally with grade I tumors (secretory meningioma). The pathology in this case confirmed a grade II meningioma. Given increased mitotic activity, despite gross total resection, the patient received postoperative radiation therapy. The role of close clinical and radiographic follow-up versus postoperative radiation for gross total resection of grade II meningiomas is currently being investigated in a randomized clinical trial.
While meningiomas can often be readily diagnosed radiographically, some important mimics should be considered when developing and prioritizing a differential diagnosis. These include other primary CNS tumors such as solitary fibrous tumors/hemangiopericytomas, dural lymphomas (which may be primary or metastatic), schwannoma, sarcoidosis and other granulomatous processes, histiocytoses such as Rosai-Dorfman disease, and dural metastases from solid tumors. The most common solid cancers that may metastasize to the dura are breast and prostate. If a patient has a known history or substantial risk of these malignancies, careful consideration should be made of the underlying etiology of a dural lesion. Often, it is impossible to differentiate these tumors radiographically. Advanced imaging studies (magnetic resonance spectroscopy or positron emission tomography [PET]), when obtained in the appropriate clinical context, may be suggestive of one etiology over another, but definitive diagnosis requires pathologic confirmation.
For many patients with meningioma, clinical and radiographic follow-up is an appropriate management plan.
The treatment of meningiomas has been extensively discussed in recent reviews. Optimal management is sometimes uncertain because many studies are noncomparative, different end points are used in different studies, and often more than one grade of tumor is included in a study. The key therapeutic modalities are detailed here, along with guidance for when they may be used. The different treatment modalities for meningioma are summarized in table 3-2.
CLINICAL AND RADIOGRAPHIC FOLLOW-UP
A substantial percentage of patients with meningioma will be diagnosed incidentally after CNS imaging is performed for an indication unrelated to the tumor (eg, motor vehicle accidents, workup for headaches or other neurologic symptoms). Although pathologic evaluation of tissue is needed to make a definitive diagnosis of meningioma, often a presumptive diagnosis can be made if the imaging is consistent with meningioma in the appropriate clinical context. In this setting, if the patient is asymptomatic, the tumor is not overly large, and the tumor lacks radiographic features that would be suggestive of a faster growth rate or higher grade, then follow-up imaging without any therapeutic intervention may be the most appropriate initial management plan. The imaging interval may initially be shorter but can often be moved, eventually, to annual scans. MRI with and without contrast is the preferred imaging modality. Ideally, this is coupled with a neurologic examination to evaluate for any findings that could be attributed to the tumor. Presumptive meningiomas adjacent to critical structures such as the venous sinuses, the optic pathways, or the pituitary gland may require more frequent monitoring with MRI and supplemental testing such as visual perimetry, magnetic resonance venography, and hypothalamic-pituitary axis blood testing.
Surgery has long served as a cornerstone in the management of meningioma. It is rare for a biopsy alone to be performed without an attempt of at least a partial resection. Surgery serves to confirm the diagnosis, establish a histologic grade, allow for molecular characterization, relieve neurologic symptomatology, and remove tumor bulk potentially curing the patient of the disease. The decision regarding whether and when to perform surgery carefully weighs the need to achieve these goals. Size, growth rate, and location are the most important tumor-specific factors to consider when deciding whether surgical intervention is warranted. Patient age and medical comorbidities also need to be considered. In general, the larger the tumor, the more likely the need for surgical resection. Surgery is the only treatment modality that effectively decreases the size of meningioma. Additionally, when a meningioma grows beyond a certain size, the ability to use other treatment modalities such as stereotactic radiosurgery becomes limited. If a tumor is growing at a rapid rate, one would anticipate the development or progression of neurologic symptoms. Surgery may be the optimal modality for alleviating the neurologic symptoms caused by growing tumor. Tumor location is important because it informs the potential types of symptoms that may develop, the risks associated with resection, and the feasibility of a total or subtotal resection. The skull base and the sagittal sinus are anatomic locations of particular importance. Because of the high risk of causing neurologic deficits and the high risk of operative complications, many skull base meningiomas are deemed to be incompletely resectable. When embarking on surgical interventions in these locations, it is typically with the understanding that residual disease will remain and will need to be either addressed with other therapeutic means or followed clinically and radiographically. The parafalcine region is a common location for meningioma. In this location, compression and/or infiltration of the sagittal sinus may exist. Analogous scenarios can be seen in relation to any of the large venous sinus structures. An understanding of the venous drainage and the presence or absence of collaterals will inform whether a resection involving sacrifice of a portion of the sinus could or should be attempted. Particular caution is paid to the posterior two-thirds of the sagittal sinus because of a high risk of venous stroke if resected in the setting of inadequate collateral outflow pathways.
The extent of tumor resection influences outcomes in patients with meningioma. The Simpson grading system for the extent of resection was developed more than half a century ago and remains in use today. Lower numbers indicate a greater degree of resection; Simpson grades 1 through 3 reflect varying degrees of “total” resection (table 3-3). Gross total resection of a WHO grade I meningioma is associated with a low risk of tumor recurrence and might be curative. As the tumor grade increases, the risk of recurrence after complete resection increases, as well. Approximately half of gross totally resected grade II meningiomas and approximately three-quarters of gross totally resected grade III meningiomas will eventually recur. For patients with subtotally resected meningioma, progression-free survival and overall survival are diminished compared with those who underwent total resection, regardless of grade.
Radiation can often provide excellent tumor control; however, it has a low likelihood of decreasing tumor size. Consequently, its role in tumors requiring substantial cytoreduction is limited. Unlike in most other CNS (and non-CNS) tumors, radiation may be used to treat meningiomas without the establishment of a pathologic diagnosis but based on the clinical and radiographic picture. The decision to use radiation and the details of its administration for meningiomas are influenced by tumor grade (if known), size, and location; patient age; medical comorbidities; newly diagnosed versus progressive/recurrent disease; and the presence or absence of surgical resection.
For grade I or presumed grade I meningiomas (diagnosed by imaging only), when radiation is used, it is most often stereotactic radiosurgery, which is a means of delivering a high dose of focal radiation to a limited field often in a single fraction. This can be performed with a linear accelerator, which is frequently used for routine fractionated radiation, or via a gamma knife, which uses a fixed cobalt source for radiation. Each device differs in specific ways. Stereotactic radiosurgery may provide excellent long-term control of WHO grade I meningiomas. The control rate and the toxicity are limited by the size and location of the target. As the size of the lesion increases, the amount of radiation that can be delivered safely in a single fraction decreases. As the amount of radiation delivered in a single fraction decreases, the control rate decreases. Additionally, as the proximity of the tumor to critical structures with a lower tolerability to radiation (eg, optic nerve, brainstem, spinal cord) increases, the ability to administer single large doses of radiation diminishes. Stereotactic radiosurgery can be used as an upfront monotherapy, as a treatment for residual disease after surgery, or to treat progressive disease, all with high rates of success in terms of control. If a lesion is adjacent to a critical structure such as the optic nerve or chiasm, stereotactic radiosurgery using multiple treatment fractions is typically used. When tumors are greater than or equal to 3 cm in diameter, most advise traditional fractionated radiation therapy in which small doses of radiation are administered to reach a cumulative high dose (often approximately 50 Gy or more for higher-grade disease) of radiation to the target. This approach minimizes toxicity. Proton therapy can also be used to treat meningiomas, especially in anatomically challenging locations, with a potentially superior safety profile. Clinical trials using this modality in the treatment of meningiomas are needed to establish efficacy and safety. It must be emphasized that many meningiomas require no therapeutic intervention (neither surgery nor radiation). The decision regarding whether, when, and how to move forward with radiation, particularly for grade I and II meningiomas, should be made using a multidisciplinary approach and patient engagement with the discussion of potential risks and benefits. This is of particular importance because there are few randomized clinical trials (particularly for grade I meningioma) to guide clinical practice. Consequently, recommendations are based on a combination of expert or consensus opinion and small nonrandomized uncontrolled clinical trials.
For WHO grade II meningiomas, complete surgical resection is the goal. If residual tumor is present postoperatively, radiation is typically used. The optimal management of completely resected grade II meningiomas is uncertain. Completely resected grade II meningiomas have an approximately 50% to 70% chance of recurring. Consequently, some experts advise avoiding postoperative radiation as half of patients will not require any subsequent treatment. Other experts argue that, despite gross total resection, the recurrence rate is high and recurrent disease is more resistant to treatment. Thus, postoperative radiation might be beneficial in this setting, although this is unproven. Therefore, treatment approaches in grade II meningioma vary by center and physician and practice experience and preferences. No class I evidence from randomized trials exists to guide these decisions at the present time. However, the specific question regarding postoperative radiation is being addressed in the ongoing NRG Oncology cooperative group phase 3 trial, which randomly assigns patients with gross totally resected grade II meningiomas to observation versus fractionated radiation to 59.4 Gy after surgery. The primary end point of this trial is progression-free survival.
WHO grade III meningiomas, both gross totally and partially resected, are routinely treated with postoperative radiation because of the very high risk of recurrence/progression. No class I evidence from randomized trials provides definitive guidance in this situation, either. Although not directly compared, fractionated radiation appears to be associated with superior control versus stereotactic radiosurgery. Fractionated radiation is typically dosed to 60 Gy. A phase 2 trial evaluated fractionated radiation to 60 Gy for grade III, progressive grade II, and incompletely resected grade II meningiomas. Overall survival at 3 years was 78.6%, and progression-free survival at 3 years was 59.2%. Doses lower than 50 Gy have been associated with inferior outcomes.
Thus far, only focal therapies such as surgery and radiation have been established as beneficial for patients with meningiomas. However, medical therapies remain an attractive strategy for this patient population as they have the potential to address an unmet clinical need, especially for patients who have exhausted all other therapeutic options. Importantly, meningiomas are thought to be on the abluminal side of the blood-brain barrier and may be more accessible to medical therapies in contrast to other parenchymal brain tumors such as metastatic lesions or gliomas where an intact or partially intact blood-brain barrier may impair drug penetration.
The study of medical therapies for meningioma is challenging secondary to several unique characteristics of the disease. There are few preclinical models for meningioma to test novel agents. It is uncertain what the optimal clinical trial end points should be when evaluating the efficacy of a medical treatment. Overall survival as an end point may not be feasible because survival in grade I meningiomas is long with a substantial number of patients not dying of disease. It is also confounded by subsequent lines of therapy including surgery and radiation. Radiographically based end points also have limitations. Thus far, the only treatment that has consistently led to a decreased radiographic tumor burden is resection. Although radiographic responses to a medical therapy would support biological activity and efficacy, expectations in this regard should remain tempered based on prior experiences in clinical trials of medical therapies for meningiomas. In turn, stability of disease and improved progression-free survival at a specific landmark in time are often considered. These have the advantage of studies reaching their conclusions more rapidly than if a survival end point is used. One of the difficulties, however, is that the time to tumor progression may still be quite long, particularly if an increase of greater than 25% in the cross-sectional area of the largest diameter (as traditionally used in high-grade gliomas) is required to define progressive disease. The Response Assessment in Neuro-Oncology working group is developing criteria for radiographic assessment of meningioma.
In addition, notable heterogeneity exists in the inclusion criteria for clinical trials. For example, the frequent inclusion of both grade II and III tumors within the same trial is problematic given different prognoses. Finally, inconsistent use of end points among clinical trials makes it difficult to compare different studies.
Thus far, no medical therapies have proven successful, although disease stability and partial responses have been observed in a small subset of patients. No biomarker has demonstrated definitive predictive value for response. The National Comprehensive Cancer Network guidelines do not advocate frontline use of medical therapies, viewing their role as limited to progressive disease after surgery and radiation. A range of medical therapies including cytotoxic agents, antiangiogenic drugs, interferons, somatostatin analogues, and targeted tyrosine kinase inhibitors have been evaluated alone or in combination. One regimen with favorable outcomes in progressive grade II/III meningiomas used a combination of the tyrosine kinase inhibitor imatinib and hydroxyurea. Although estrogen and progesterone receptor expression is common in meningiomas, targeting these receptors has not proven successful. Current interest centers on tyrosine kinase inhibitors targeting specific cellular signal transduction pathways known to be active in subtypes of meningioma. Ongoing clinical trials are using novel agents targeting the SMO, AKT, and NF2 pathways, the MEK pathway, and the CDK-p16-Rb pathway. The results of the FAK inhibitor (GSK2256098) targeting NF2 in the phase 2 Alliance for Clinical Trials in Oncology trial have been reported. Although radiographic responses were limited, 6-month progression-free survival (83% in grade I meningiomas, 33% in grade II/III meningiomas) was promising when compared with historical controls. GSK2256098 proved well tolerated in this patient population.
Pituitary tumors are commonly encountered in neurologic practice. Neurologists should be familiar with the management of these common, predominantly nonmalignant tumors.
Pituitary adenomas are the most common lesions observed in the sellar region and account for up to 10% of intracranial neoplasms, making them one of the more common CNS tumors. Several other disorders can be present in the sellar region that are sometimes difficult to distinguish from pituitary adenomas by imaging alone (table 3-4). Tumor types frequently encountered in this location include meningiomas and craniopharyngiomas. Few studies addressing the incidence and prevalence of pituitary adenomas in the population exist. Similar to meningiomas, these tumors are frequently found incidentally when imaging studies are done for a variety of clinical reasons. It is estimated that the incidence rates for all pituitary adenomas range from 7 per 100,000 to 92 per 100,000 with a prevalence of approximately 1000 per 100,000.
The etiology of pituitary adenoma is not fully understood. Classic oncogenic mutations that are found in other cancers are not commonly observed in pituitary adenomas. However, specific genes and mutations may play a role in the development of some subtypes of pituitary adenomas. Loss-of-function mutations in the MEN1 tumor suppressor gene seem to be responsible for tumors forming in different glands including the pituitary gland. This seems to be specific for patients with multiple endocrine neoplasia syndrome. However, mutations in this gene alone do not cause sporadic pituitary adenomas. Another gene postulated in the pathophysiology of pituitary tumors is GS alpha. An activating mutation of GS alpha is observed in approximately 40% of pituitary adenomas. Mutations in this gene play a role in both cell proliferation and excessive growth hormone secretion by the adenomas. Finally, mutations in AIP (aryl hydrocarbon receptor interacting protein) are associated with familial pituitary adenomas frequently diagnosed in adolescents and young adults.
Pituitary adenomas are typically classified by functional subtype, size, and invasiveness. Size criteria most commonly divide pituitary adenomas into two distinct groups: those smaller than 10 mm in diameter are microadenomas, and those 10 mm or larger in diameter are macroadenomas (case 3-2).
A 67-year-old man presented with transient right upper extremity paresthesia. Neurologic examination was unremarkable. He underwent brain imaging with MRI, which demonstrated a left-sided nonenhancing lesion in the sella. The lesion contacted the inferior aspect of the optic chiasm (figure 3-2).
This radiographic finding was considered an incidental finding unrelated to the presenting right arm paresthesia. However, the patient underwent transsphenoidal endoscopic resection of the lesion, and pathology confirmed a pituitary adenoma, gonadotroph type (immunostains were negative for adrenocorticotropic hormone [ACTH], thyroid-stimulating hormone [TSH], prolactin, and luteinizing hormone, and positive for follicle-stimulating hormone). The patient did well after surgery with no radiographic evidence of residual tumor (figure 3-2). No additional tumor-directed therapy was provided.
In this case, the patient’s asymptomatic pituitary adenoma was discovered incidentally during workup for transient ischemic attack. This is a common clinical scenario. The tumor met the criterion for macroadenoma (larger than 10 mm in diameter). Even though the patient did not have hormonally driven symptoms or a visual field deficit, he was referred for resection given the size of the tumor and its contact with the optic chiasm. Gross total resection was achieved, and no additional tumor-directed therapy was needed given the histologic diagnosis of pituitary adenoma, gonadotroph type. After surgery, the patient was monitored closely for pituitary dysfunction.
Clinical symptoms and signs related to pituitary adenomas can be divided into those secondary to local mass effect (nonsecreting/nonfunctioning pituitary adenomas) and those secondary to production of specific hormones by the tumor (secreting/functioning pituitary adenomas). Approximately one-third of pituitary adenomas are nonfunctioning. However, this may be an underestimate as many small nonfunctioning pituitary adenomas likely go undiagnosed. With respect to the mass effect on surrounding structures, of greatest concern is the potential compression of the adjacent optic chiasm and optic nerves. This can lead to visual loss and blindness. Often, bitemporal hemianopia is the first neurologic deficit noted. Because of the potentially irreversible nature of visual deficits, patients with pituitary adenomas are often followed by an ophthalmologist or neuro-ophthalmologist with serial visual field testing. The growing mass may also be associated with increased intracranial pressure and its associated symptoms of positional headache, nausea, and diplopia. Finally, compression of the pituitary gland itself or the pituitary stalk can negatively impact output from the pituitary or the hypothalamic-pituitary axis. Compression of the pituitary gland may be associated with diminished secretion of adrenocorticotropic hormone (ACTH), thyroid-stimulating hormone (TSH), luteinizing hormone, follicle-stimulating hormone, prolactin, growth hormone, or melanocyte-stimulating hormone alone or in combination. Compression of the pituitary stalk can lead to impairment of the negative-feedback dopamine signal from the hypothalamus to the pituitary gland. With the loss of this negative signal, there can be an excess secretion of prolactin (“stalk effect”). However, the elevated prolactin levels associated with this stalk effect are typically lower than those observed with functioning prolactinomas.
Functioning pituitary adenomas secrete hormones related to their cell of origin. Mixed-cell adenomas secrete more than one hormone. Approximately half of functioning pituitary adenomas are prolactinomas. This excess of prolactin can be associated with galactorrhea in both women and men, gynecomastia in men, breast atrophy in women, decreased libido, oligomenorrhea/amenorrhea, impotence, infertility, osteoporosis, and alopecia. The second most common functioning pituitary adenoma is the somatotropic subtype, which secretes growth hormone. In adults, this manifests as acromegaly with its associated increase in the size and coarseness of facial features, particularly the nose, ears, and chin, as well as an increase in the size of the hands and feet. In those who have not undergone full closure of growth endplates in their bones, gigantism develops. Less frequently encountered functioning adenomas are corticotropic pituitary adenomas, which secrete ACTH. This leads to Cushing disease, which is associated with weight gain and fat redistribution, particularly in the face (moon facies) and in the upper back/neck (buffalo hump). Gonadotroph pituitary adenomas secrete luteinizing hormone and follicle-stimulating hormone. While functional, these adenomas may be clinically silent as the excess hormone is not typically associated with clinical symptomatology.
The recommended diagnostic workup for a patient with a pituitary lesion is summarized in table 3-5.
Treatment modalities used for the management of pituitary tumors include medical therapy, surgery, and radiation.
Medical therapies are an option for hyperfunctioning pituitary adenomas, although efficacy varies widely. Prolactinoma, the most common type of hyperfunctioning pituitary adenoma, can be controlled by the use of dopamine agonists, specifically cabergoline and bromocriptine. Medical therapy is usually started initially, especially for smaller lesions that are not causing compressive symptoms related to the optic pathways. Dopaminergic agents inhibit cellular proliferation and prolactin secretion, leading to tumor shrinkage and improvement of clinical symptoms. Decreasing prolactin levels can be sustained for prolonged periods of time, and radiographic tumor regression can be observed in up to 62%, resolution of galactorrhea in up to 86%, and resumption of menstruation in up to 78%. Cabergoline appears to be effective even in larger tumors; it is also associated with a better tolerance due to fewer side effects compared with bromocriptine. It should be noted that the chronic use of dopamine agonists might be associated with an increased risk of developing cardiac abnormalities, including tricuspid regurgitation. The duration of therapy varies; guidelines suggest that patients treated for 2 years or longer and who have achieved normalization of prolactin levels, as well as tumor resolution on MRI, may be considered for a trial of medication discontinuation.
In patients with growth hormone–producing tumors, medical therapy is limited, and surgery is the initial treatment of choice. In selected cases, somatostatin analogues might be useful. Both octreotide and lanreotide have a high affinity for somatostatin receptors on somatotroph cells and can induce biochemical remissions. In turn, optimal hormonal control can reduce mortality and comorbidities associated with acromegaly. In clinical trials, 75% of acromegalic patients can achieve a reduction in tumor size and biochemical control when treated with somatostatin analogues. In patients who do not respond to somatostatin analogues, pegvisomant, a growth hormone receptor antagonist, may be useful. This agent can be used as monotherapy or in combination with somatostatin analogues. In addition, cabergoline may be useful in some patients, especially when insulinlike growth factor-1 levels are mildly elevated or in patients with tumors co-secreting prolactin.
The treatment of Cushing disease continues to evolve. Medical therapy is usually considered as the interim modality while other options (surgery and/or radiation therapy) are being contemplated. In the past, agents blocking the synthesis of cortisol (eg, metyrapone, ketoconazole, mitotane) were widely used. The US Food and Drug Administration (FDA) has approved two agents to control hypercortisolism associated with Cushing disease: mifepristone and pasireotide. These agents are indicated for patients who cannot undergo surgical treatment or in whom surgery was not curative. Their long-term efficacy and safety are being investigated.
For patients with thyrotropin-stimulating hormone–producing pituitary adenomas (less than 1% of pituitary adenomas), surgery is the treatment of choice. Some of these tumors may not be surgically curative because of their size or invasiveness. In these cases, somatostatin analogues can be considered in an effort to control the symptoms of hyperthyroidism.
Typical indications for surgery in nonfunctioning adenomas include progressive visual loss secondary to optic chiasm compression, progressive hypopituitarism, clinical signs and symptoms of cavernous sinus compression, and intractable headaches that can be linked to the tumor. Most hormonally active tumors are typically managed by using medical therapy (as described earlier), but surgery may be indicated in some cases. Patients who do not respond to medical therapy due to poor efficacy (eg, cystic variants of prolactinomas respond poorly to medical therapy) or due to intolerable side effects may also be candidates for surgical therapy.
Surgery is first-line therapy for growth hormone–secreting tumors and for patients with Cushing disease who have ACTH-secreting pituitary tumors. When surgical therapy is indicated, minimally invasive transnasal, transsphenoidal approaches are usually recommended. The minority of lesions not amenable to this technique are treated by craniotomy (4% to 5%).
Radiation therapy is typically used for recurrent, previously resected, nonfunctioning adenomas if further surgery is not feasible and for newly diagnosed patients with unresectable tumors. Both stereotactic radiosurgery and fractionated radiation therapy are used in this setting. Stereotactic radiosurgery is the treatment of choice for lesions smaller than 3 cm in diameter and distant from the optic chiasm and optic nerves. A dose of 15 Gy to 18 Gy for nonfunctioning lesions and 20 Gy or more for secretory tumors is often recommended. When fractionated radiation therapy is used for the remaining indications, doses between 45 Gy and 54 Gy are typically used. Important factors need to be considered for patients with secretory adenomas. Treatment technique, dose of radiation, and timing are critically important. Medical therapies should be discontinued prior to treatment with radiation because some of these agents may render radiation therapy less effective. Tumor arrest rates from radiation can be high in patients with secretory tumors, but the time to biochemical cure can be prolonged and ranges from 9 months to several years. Late effects of radiation should be considered and reviewed with patients. One such effect, hypopituitarism, occurs in approximately 70% of patients by 10 years and will require hormone replacement therapy. Other late complications include secondary malignancies (meningioma, sarcoma, high-grade glioma) and cerebrovascular complications. For specific indications for radiation therapy for nonfunctioning adenomas, see table 3-6.
Pituitary carcinomas are malignant tumors arising from the pituitary gland. These tumors account for approximately 0.1% of pituitary tumors. They can develop in the presence of a previous nonmalignant adenoma. The average latency period from adenoma to carcinoma is approximately 6 years but can be as long as 18 years. Pituitary carcinomas are often secretory; ACTH is most frequently secreted, followed by prolactin. Treatment involves surgery, radiation therapy, and less commonly chemotherapy. Temozolomide can produce high response rates in pituitary carcinomas, and these can be durable for up to 2 years.
Craniopharyngiomas are rare, grade I, suprasellar tumors that arise from nests of epithelium derived from the Rathke pouch. These tumors may grow superiorly and posteriorly compressing and, to a lesser degree, infiltrating adjacent brain and the optic pathways. Craniopharyngiomas may also grow inferiorly impacting the hypothalamic-pituitary axis resulting in endocrinopathies.
Craniopharyngiomas are rare compared with meningiomas and pituitary adenomas. Approximately 600 new cases are diagnosed in the United States each year, totaling 0.8% of all newly diagnosed CNS tumors. The median age at diagnosis is in the early-middle forties. The incidence is slightly higher in those who are Black versus those who are White. No clear sex difference exists in the incidence of craniopharyngiomas. Although the details regarding histologic subtypes are not tracked by the Central Brain Tumor Registry of the United States, the adamantinomatous subtype occurs more commonly in the pediatric population (with a second peak in incidence in the age range of 40 to 60 years), whereas the papillary subtype occurs more frequently in adults. Median overall survival estimates vary because most studies have a limited duration of follow-up. In one study of pediatric patients, 10-year survival was 96%.
Craniopharyngiomas are driven by mutually exclusive clonal mutations in either BRAF or CTNNB1.BRAF mutation is associated with the papillary subtype, whereas the CTNNB1 mutation occurs in the majority (in up to 90%) of adamantinomatous subtypes. Overall, these tumors have a relatively low tumor mutational burden (0.9 mutations per megabase) when compared with other neoplasms. The genetic simplicity, the high frequency of targetable oncogenic driver mutations, and their clonal presence throughout the tumor make craniopharyngioma an attractive candidate for targeted therapies.
The BRAF mutation observed in craniopharyngiomas is the canonical V600E mutation observed in melanoma and other malignancies. This mutation leads to constitutive activation of the mitogen-activated protein kinase (MAPK) pathway. This in turn leads to activation of MEK and ERK, which are central to regulating cell growth, proliferation, and differentiation.
CTNNB1 encodes β-catenin, a protein that is a subunit of the cadherin complex and plays a role in cell-cell adhesion and gene transcription. Cadherins are a central component of cell-cell junctions, which enable cells to adhere to one another, and these proteins also modulate the interactions between the cell surface and cytoskeleton. Mutation of β-catenin leads to dysregulation of the developmental WNT signaling pathway.
Papillary craniopharyngiomas typically grow as solid masses unlike their more cystic adamantinomatous counterparts. However, the presence of a cyst is not pathognomonic for adamantinomatous craniopharyngioma. Patients may present with nonlocalizable symptomatology indicative of increased intracranial pressure. Patients with craniopharyngioma may also develop focal symptoms and signs depending on the underlying neuroanatomy. Because of the relative proximity to the optic pathways and pituitary gland, symptoms of visual impairment (including bitemporal hemianopia) and endocrinopathy may occur. With growth into the suprasellar region, craniopharyngiomas may result in hypothalamic dysfunction and, with further growth, frontal lobe dysfunction. Hypothalamic dysfunction may include abnormalities of appetite, the sleep-wake cycle, libido, salt regulation, growth (in prepubertal patients), and cognition/behavior. Ophthalmologic evaluation with visual perimetry and serum hormonal profiling should be a component of the initial and subsequent evaluations.
MRI of the brain is typically performed in the evaluation of patients presenting with the symptoms described in the previous paragraph. Craniopharyngiomas are enhancing lesions arising from the suprasellar region (figure 3-3). These tumors can compress the frontal lobes upward, infiltrating inferiorly into the sella and beyond leading to compression of the optic chiasm and nerves. The lesions may be solid, cystic, or both; cystic lesions are more common in adamantinomatous craniopharyngiomas. Although no radiographic characteristics can reliably differentiate the subtypes of craniopharyngioma, patient age and certain radiographic features such as cystic formation can be suggestive.
Treatment options for craniopharyngiomas include surgery, radiation, and medical therapy.
The cornerstone of management of these tumors is maximal safe resection. This provides critical diagnostic information and therapeutic benefit. In the current molecular era, the subtype of craniopharyngioma can be confirmed. In addition, resection can result in cytoreduction with relief of the mass effect associated with these tumors. However, given the typical location of craniopharyngiomas at the base of the skull and adjacent to a number of critical structures, a complete resection can be difficult, although the success rate of achieving a gross total resection has improved over time.
Craniotomies as well as endoscopic skull base approaches are used in the management of craniopharyngiomas. Endoscopic approaches are associated with higher rates of gross total resection and a lower incidence of hypothalamic dysfunction. This is balanced against a higher incidence of CSF leaks with the endoscopic approach.
Radiation therapy is often used when treating residual or, more frequently, recurrent disease. Both the solid and cystic components of the tumor, as well as a margin encompassing surrounding tissue, are targeted. With the use of fractionated, photon-based therapy, doses of 54 Gy to 55.8 Gy are typical. Stereotactic radiosurgery has also been used for residual or recurrent disease. The size of the target lesion and the adjacent critical structures are considered when deciding on the use of stereotactic radiosurgery.
Several aspects make proton beam therapy an attractive option in craniopharyngioma. These include the relatively circumscribed noninfiltrating nature of the tumor, the proximity to critical structures with lower tissue tolerance for radiation, the younger age of patients, and the expected prolonged survival. However, no randomized studies have compared photon and proton radiation in this patient population.
Medical therapies have, as of yet, not been established as the standard treatment for craniopharyngioma. Early studies evaluated the role of immunotherapeutic approaches, such as the use of interferon alfa. Targeted therapies may improve outcomes in the molecular subtypes of craniopharyngioma. Several studies are underway targeting the β-catenin pathway in craniopharyngiomas. Interleukin-6 is elevated within the cysts of adamantinomatous craniopharyngiomas, and it is being targeted with the monoclonal antibody tocilizumab in an early-phase clinical trial. In contrast, radiographic responses of papillary craniopharyngioma with BRAF V600E mutations to BRAF inhibitors alone or in combination with MEK inhibitors have been well documented (figure 3-4). However, whether these targeted therapies improve progression-free or overall survival for this type of tumor is unknown. A multicenter cancer network study (NCT03224767) is ongoing, testing the combination of a BRAF inhibitor (vemurafenib) with a MEK inhibitor (cobimetinib) in BRAF V600E–mutated, papillary craniopharyngiomas.
Glioneuronal tumors are rare, histologically mixed neuronal and glial tumors. These tumors are frequently associated with pharmacoresistent seizures and often occur in children and young adults. Glioneuronal tumors are most often WHO grade I; however, rare high-grade variants with poor prognosis occur.
Dysembryoplastic Neuroepithelial Tumor
Dysembryoplastic neuroepithelial tumor (DNET) is a grade I glioneuronal neoplasm typically associated with epilepsy and occurring mainly in children and young adults with a slight male predominance. The tumor is commonly located in the temporal lobe, usually in the cortex, and is characterized radiographically by multiple nodules. Pathologically, it is characterized by columns oriented perpendicularly to the cortical surface and formed by bundles of axons lined by small cells resembling oligodendrocytes. Between these columns, neurons are “floating” in a pale eosinophilic matrix with scattered astrocytes. In approximately 90% of patients with DNETs, seizures begin before the age of 20, and the diagnosis is suspected after brain imaging. Imaging typically reveals a cortically based lesion (or lesions) without surrounding edema or mass effect. The tumor has a multicystic, multinodular appearance, and calcifications are common. Approximately 30% of DNETs enhance on postcontrast imaging (figure 3-5). Resection is the treatment of choice, and this tumor is associated with an excellent prognosis. Even incomplete resections can result in long periods without disease progression. Occasionally, these tumors exhibit more aggressive behavior, in which case reoperation might be necessary. Radiation therapy is typically reserved for recurrent disease with aggressive features. Currently, chemotherapy has no role in the management of DNETs. However, as noted in cases with specific molecular alterations in BRAF or NTRK, targeted therapies hold promise.
Gangliocytoma and Ganglioglioma
Gangliocytoma is a rare, well-differentiated, slow-growing neuroepithelial tumor composed of neoplastic mature ganglion cells. These cells may have dysplastic features including multiple nuclei. These tumors usually stain positively for neuronal markers (eg, neurofilament, synaptophysin) and for oncofetal CD34 antigen. Gangliocytoma is a WHO grade I tumor, mostly affecting children, and accounts for 0.1% to 0.5% of all CNS tumors. Gangliocytoma can occur throughout the CNS with the dysplastic forms commonly found in the cerebellum (Lhermitte-Duclos disease). Seizures are the most common presenting symptom, occurring in 65% to 85% of patients with gangliocytoma. On imaging, the tumors are well-circumscribed solid or cystic masses with occasional mural nodules and calcifications. Resection is the first and preferred treatment, and gross total resection is the best predictor of prolonged survival. Patients with tumors in the midline, brainstem, and spinal cord, where complete resection is not always possible, have a higher risk of recurrence and death. As patients with WHO grade I gangliocytoma can survive for many years, the achievement of seizure freedom is one of the main goals of surgery. Radiation therapy has a limited role in gangliocytoma. Chemotherapy has not demonstrated benefit and is typically reserved for rare patients with refractory or recurrent tumors. The chemotherapeutic drugs most commonly used include nitrosoureas, temozolomide, etoposide, carboplatin, and cyclophosphamide.
Ganglioglioma is a well-differentiated, slow-growing, glioneuronal neoplasm composed of a combination of mature neoplastic ganglion cells and neoplastic glial cells resembling astrocytoma or oligodendroglioma. Astrocytic forms typically stain positively for glial fibrillary acidic protein. Most gangliogliomas are WHO grade I; however, some may have anaplastic features in the glial component with a high proliferation index, vascular proliferation, and necrosis. These cases are designated WHO grade III and usually have a poor prognosis. Gangliogliomas usually present in the temporal lobe in children and young adults. As with gangliocytomas, seizures are the most common presenting symptoms. Imaging characteristics for low-grade ganglioglioma are similar to gangliocytoma (figure 3-6). Anaplastic ganglioglioma is often more infiltrative on MRI and typically has more contrast enhancement and surrounding edema. Molecular alterations in gangliogliomas frequently include BRAF pathway activation and gene fusions. Similar to gangliocytoma, resection is the first treatment to offer to patients. Gross total resection is usually feasible and results in excellent outcomes. Gangliogliomas may undergo malignant transformation at the time of progression. If possible, recurrent tumors should be resected to confirm pathologic and molecular diagnosis. Radiation therapy for ganglioglioma is mainly reserved for patients who did not have an initial gross total resection of low-grade lesions or for patients who experience anaplastic progression. The dose range is between 45 Gy and 54 Gy for low-grade lesions and up to 60 Gy for atypical or anaplastic lesions. Gangliogliomas may harbor BRAF V600E mutations and TLE4-NTRK2 fusions, and these alterations should be screened for in the molecular profile. BRAF inhibitors or NTRK inhibitors have been documented to result in radiographic responses (figure 3-7). Larotrectinib and entrectinib are NTRK inhibitors approved by the FDA for any tumor with an NTRK fusion and could be used to treat any type of glioneuronal tumor with such an alteration. Response rates have been reported in histology-agnostic clinical trials of these agents, underlining the importance of screening for these rare targetable abnormalities in tumors lacking other favorable systemic treatment options.
Meningiomas and pituitary adenomas are frequently encountered in neurology practice. These predominantly nonmalignant tumors collectively account for most primary brain tumors. Diagnostic approaches typically involve brain MRI with contrast and visual perimetry and hormonal studies in the case of pituitary adenomas. Occasionally, advanced imaging and vascular imaging (angiography) may be needed for surgical planning. Asymptomatic lesions may be followed without therapy for as long as the tumors are stable. Different factors help clinicians decide on the timing and type of intervention. A combination of surgical, radiation, and medical therapies is used in the management of these types of primary tumors, and a multidisciplinary team is needed to plan optimal therapy.
Craniopharyngiomas are rare but, because of their location adjacent to critical structures, can be associated with substantial morbidity. The papillary and adamantinomatous subtypes of craniopharyngiomas are associated with BRAF or CTNNB1 mutations, respectively, and targeted agents are being explored.
Rare low-grade glioneuronal tumors including DNET, gangliocytoma, and ganglioglioma typically follow an indolent clinical course. Resection is the preferred therapy for these tumors and can often be curative. Molecular alterations in BRAF and NTRK are potentially targetable with medical therapies.
- Meningiomas are the most common primary brain tumor.
- Most meningiomas grow slowly and may be followed radiographically as the initial management approach as long as they are asymptomatic.
- Surgery is the primary treatment for meningioma in most cases, and recurrence rates are associated with the extent of resection and the grade of the tumor.
- Radiation therapy is usually reserved for unresectable meningiomas, incompletely resected meningiomas, recurrent meningiomas, and higher-grade meningiomas.
- Cytotoxic and hormonal medical therapies are largely ineffective in meningioma.
- Novel medical therapies for meningioma including tyrosine kinase inhibitors are under study.
- Pituitary adenomas are the second most common primary brain tumor and are frequently discovered on imaging incidentally.
- Pituitary adenomas smaller than 10 mm in diameter are termed microadenomas whereas pituitary adenomas 10 mm in diameter or larger are termed macroadenomas.
- Common categories of pituitary adenomas include functioning/secreting tumors and nonfunctioning/nonsecreting tumors.
- Medical therapies are commonly used for functioning/secreting pituitary adenomas as the primary treatment.
- Large pituitary adenomas may cause compression of adjacent critical structures including the optic pathways and often require prompt surgical intervention.
- Radiation therapy is used for patients with unresectable pituitary adenomas, recurrent pituitary adenomas, or those not responding to medical therapy.
- Craniopharyngiomas are low-grade, slow-growing tumors arising from the suprasellar region.
- Craniopharyngiomas can be divided into two subtypes, BRAF mutated (papillary) and CTNNB1 mutated (adamantinomatous), based on their molecular alterations.
- Current management of craniopharyngiomas consists of resection by either a transcranial or an endoscopic approach.
- Surgery for craniopharyngioma may be followed by radiation, with either protons or photons, for recurrent or residual disease.
- Targeted therapies for craniopharyngioma remain investigational but hold substantial promise.
- Glioneuronal tumors are most often World Health Organization grade I; however, rare high-grade variants with poor prognosis occur.
- Dysembryoplastic neuroepithelial tumors (DNETs) and other glioneuronal tumors are associated with a high incidence of seizures.
- Resection is the primary treatment modality for glioneuronal tumors, and complete resection can often be curative.
- Resection is the primary treatment modality for glioneuronal tumors, and complete resection can often be curative.
- Molecular alterations including BRAF mutations and NTRK fusions occur in the majority of glioneuronal tumors and should be screened for; targeted agents against these alterations may be effective.
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