HIGH-GRADE GLIOMAS IN ADULTS

A.  Course of disease.

The World Health Organization (WHO) stratifies “malignant” or “high-grade” gliomas (HGGs) into histologic grade 3 tumors (anaplastic astrocytoma, anaplastic oligodendroglioma, and anaplastic oligoastrocytoma) and grade 4 glioblastoma (GBM) based on the degree of hypercellularity, nuclear pleomorphism, mitoses, microvascular proliferation, and necrosis. GBM is the most common glioma in adults, accounting for at least 50% of all cases. Unfortunately, this tumor is also the most deadly. Grade 3 tumors together account for approximately 20% of adult gliomas. There is a slight male predominance. Median age at diagnosis for GBM is 55 to 60 years and for grade 3 tumors 40 to 45 years. Recent epidemiologic evidence suggests an increasing incidence of GBM, especially among elderly persons. Approximately 5% to 8% of patients with GBM had a prior histologically proven diagnosis of astrocytoma or other lower-grade glioma. These patients with “secondary” GBM are on average younger than the great majority of patients with de novo or “primary” GBM.

Patients with HGG generally present with a fairly short history of some combination of headache, seizures, and focal neurologic symptoms determined by the tumor location. HGG appears on magnetic resonance imaging (MRI) scans as an irregular mass lesion with heterogeneous or ring enhancement (Fig. 57.1). Central necrosis with peripheral ring enhancement is more likely GBM than a grade 3 tumor. There is a predilection for infiltrating tumor to extend across the corpus callosum or to spread along other major white matter pathways. T2-weighted and fluid-attenuated inversion recovery (FLAIR) images typically show hyperintense signal extending in an irregular shape for considerable distance beyond the margins of contrast enhancement. In most if not all patients there are infiltrating tumor cells within and beyond the area of abnormal T2/FLAIR signal. The variable topography and distance of tumor cell infiltration are serious obstacles to attempts at surgical resection or other “focal” therapies for these tumors.

B.  Therapy.

Standard treatment for patients with newly diagnosed GBM is maximal tumor resection consistent with preservation of neurologic function, followed by limited-field radiation therapy (RT), and for most patients chemotherapy begun during or after RT. Several modern techniques facilitate the aggressive resection of gliomas and reduce the risk of neurologic morbidity for selected patients. Preoperative functional MRI, diffusion-tensor MRI, and intraoperative cortical and subcortical mapping can determine the tumor’s proximity to and involvement of motor and speech structures. Intraoperative MRI allows the surgeon to assess the degree of resection and possibly continue the resection to remove more residual tumor.

FIGURE 57.1 Axial T1-weighted MRI scan of a patient with a right parietal GBM, showing heterogeneous tumor enhancement, moderate surrounding cerebral edema and associated mass effect, and extension of tumor enhancement across the corpus callosum into the deep left hemisphere. GBM, grade 4 glioblastoma; MRI, magnetic resonance imaging.

For patients with symptomatic tumor mass effect, aggressive surgery usually improves neurologic function. All published data regarding the impact of extent of initial resection of GBM on overall survival are retrospective and nonrandomized. Most (not all) retrospective studies show a survival advantage for patients who undergo an “aggressive” resection. The cutoff value of how much of the enhancing tumor needs to be resected to impact survival ranges from 75% to almost 100% in various studies. In studies where multivariate analysis showed the extent of resection to be an independent prognostic factor, the impact on survival was nearly always less than that for patient age, tumor histology, and pretreatment performance status.

Standard postoperative RT for GBM is 60 Gy “focal” or “limited-field” RT delivered to a target encompassing a 2 to 3 cm margin around the radiographically visible tumor area.

GBM occasionally spreads through the leptomeninges or recurs far from the initial tumor site, but for the vast majority of patients the ultimate cause of death is tumor recurrence within the initial RT target area. There is no evidence that higher doses of fractionated RT or a “boost” of stereotactic radiosurgery or brachytherapy in addition to conventional RT provide any survival advantage.

Based on a randomized prospective study, the current standard chemotherapy regimen for patients with newly diagnosed GBM is daily oral temozolomide taken concurrently during RT, followed by six or more monthly cycles of temozolomide after completion of RT. Temozolomide is an alkylating agent, which has excellent oral bioavailability and shows good penetration across the blood–brain barrier. Noncumulative myelosuppression is the dose-limiting toxicity. For selected GBM patients another chemotherapy option is surgical implantation of carmustine-containing wafers at the time of initial resection.

Nearly all GBMs recur despite aggressive multimodality treatment. The median time to tumor progression after initial diagnosis of GBM is 6 to 9 months. For selected patients with relatively young age, good performance status, and accessible lesions, a second surgical resection may improve neurologic function, and modestly prolongs survival. Depending on tumor size and location, some patients may benefit from stereotactic radiosurgery or a second course of fractionated RT. For many if not most patients with recurrent or progressive GBM, further surgery or RT is judged not to be feasible or advisable. Systemic chemotherapy options for recurrent GBM include a retrial of temozolomide, carboplatin, or lomustine.

In the United States the most commonly used drug treatment for recurrent GBM is bevacizumab, a humanized monoclonal antibody against vascular endothelial growth factor. In addition to its antiangiogenic and antitumor effect, bevacizumab is a potent inhibitor of vascular permeability and cerebral edema. Two large phase 3 randomized studies of patients with newly diagnosed GBM did not show an overall survival advantage among those who received upfront bevacizumab in addition to RT and temozolomide, though bevacizumab did prolong median time to tumor progression. At this time bevacizumab is not considered standard care for newly diagnosed GBM patients.

NovoTTF treatment is a portable device that applies an electrical field to the tumor area through the scalp. There is no systemic or neurologic toxicity. This device is approved in the United States for treatment of patients with recurrent GBM, and has recently been approved for patients with newly diagnosed GBM following initial RT and temozolomide.

Current clinical trials for treatment of GBM include agents that inhibit growth factor receptors, intracellular or extracellular signaling pathways, angiogenesis, or tumor cell migration. Immunotherapy trials include autologous dendritic cell vaccination, immunologic “checkpoint inhibitors,” and active immunization with mutant epidermal growth factor receptor protein. Several viruses including poliovirus have been genetically modified to selectively attack tumor cells rather than normal neurons.

The treatment of patients with newly diagnosed grade 3 glioma is similar to that for patients with GBM, that is, maximal safe surgical resection followed by fractionated RT and chemotherapy. For patients with newly diagnosed anaplastic astrocytoma, the efficacy of concurrent RT + temozolomide, followed by monthly temozolomide has not been definitively proven, but it is common practice to administer the same regimen as for patients with GBM.

Two prospective randomized studies of patients with newly diagnosed anaplastic oligodendroglioma showed that adding procarbazine/CCNU/vincristine chemotherapy (the PCV regimen) to surgery and RT significantly prolonged time to tumor progression and overall survival. The benefit of PCV was strongly linked to the presence of chromosome 1p/19q codeletion and to isocitrate dehydrogenase (IDH) mutation, though the genetic markers are not an absolute predictor of response or outcome. It is common practice to administer temozolomide rather than PCV for these patients, because of temozolomide’s greater simplicity and better toxicity profile, though the relative efficacy of temozolomide versus PCV is not clearly known. It is also not clear whether chemotherapy (PCV or temozolomide) without RT could be an equally effective option for patients with anaplastic oligodendroglioma and a favorable genetic profile.

Supportive care for patients with HGG includes varying doses of dexamethasone to reduce peritumoral edema and increase neurologic function, and aggressive treatment of pain and/or depression if they occur. The concepts and strategies for treating glioma-associated seizures are the same as those for treating localization-related epilepsy in general. There is no definite evidence that any particular antiepileptic drug is differentially effective for glioma-related seizures versus epilepsy caused by other structural brain lesions. For patients taking dexamethasone or receiving chemotherapy agents metabolized by the liver, the non-enzyme-inducing antiepileptic drugs (e.g., levetiracetam or valproate) may offer fewer drug interactions than enzyme-inducing drugs (e.g., phenytoin or carbamazepine). For patients who do not have seizures at initial presentation, there is no definite evidence to support long-term prophylactic antiepileptic medication.

C.  Prognosis.

Patient age, tumor histology, and performance status are independent prognostic factors for survival of patients with HGG. These are useful as predictors of individual patient outcome and are critically important in designing and interpreting clinical trials. With standard multimodality treatment, patients with GBM have a median survival of about 18 months and only about 25% survive 24 months. Patients with anaplastic astrocytoma have a median survival of 3 to 4 years, and for those with anaplastic oligodendroglioma 4 to 6 years. Median survival is inversely proportional to age throughout all decades of adult life; older patients have a worse prognosis. Patients with a better performance status at the time of diagnosis have a better survival outlook than patients who present with severe neurologic impairment.

Gene expression profiling studies have identified four major molecular subclasses of GBM based on their transcriptional patterns: classical, proneural, mesenchymal, and neural. Patients with proneural GBM have a somewhat better survival outcome than those in the other classes. The proneural group contains an over-representation of patients with secondary GBM. At the present time the molecular subclass of GBM does not influence treatment choices for individual patients.

The molecular genetic profile of grade 3 (and grade 2) gliomas has a major impact on patient outcome and is becoming an integral part of tumor classification. Approximately 75% of grade 2 or grade 3 gliomas of any histologic type (astrocytoma, oligodendroglioma, or oligoastrocytoma) show mutation of the gene encoding IDH. This mutation is believed to be a very early event in tumorigenesis. Tumors with IDH mutation and mutation of the p53 tumor suppressor gene tend to show astrocytic differentiation, whereas tumors with IDH mutation and codeletion of chromosome 1p and 19q tend to have an oligodendroglial phenotype. P53 mutation and chromosome 1p/19q codeletion are almost always mutually exclusive. Grade 2 or grade 3 gliomas can roughly be divided into three subgroups based on their IDH and 1p/19q status: (1) tumors with IDH mutation and 1p/19q codeletion have the most favorable survival outcome; (2) tumors with IDH mutation but not 1p/19q codeletion (nearly all with p53 mutation) have an intermediate survival outlook; and (3) tumors with wild-type IDH and not 1p/19q codeletion are most often classified as anaplastic astrocytoma, and have other molecular genetic features resembling GBM; these tumors have the least favorable outcome. Recent studies show that stratification of clinical outcome on the basis of IDH/chromosome 1p/19q status is more accurate than prediction based on histologic phenotype.

LOW-GRADE GLIOMAS IN ADULTS

A.  Course of disease.

Low-grade gliomas (LGGs) in adults include WHO grade 2 astrocytoma, oligodendroglioma, and mixed oligoastrocytoma. Together these comprise about 30% of all gliomas in adults. LGGs should not be considered “benign” tumors, as they generally lead to a fatal outcome. Low-grade astrocytomas are poorly circumscribed and are characterized by diffuse infiltration of atypical astrocytes with hyperchromatic nuclei. Gross and microscopic boundaries are difficult to define. Immunocytochemical staining for the intermediate filament glial fibrillary acidic protein is a marker for astroglial derivation. The classic histologic features of oligodendrogliomas are tumor cells with uniform round nuclei and clear perinuclear halos (“fried-egg appearance”), with a “chicken wire” network of branching capillaries. Microcalcifications and microcystic spaces are common. Mixed oligoastrocytomas contain some tumor cells with astrocytic morphology and other cells with oligodendrocytic morphology. The two elements are either spatially separate, or more often intermingled.

The median age at diagnosis of supratentorial LGG in adults is 35 to 40 years. There is a slight male predominance. In the era of MRI scanning at least 70% of patients with LGG present only with seizures, and no headache or other neurologic symptoms. LGG usually appears as a poorly demarcated mass lesion hypointense on T1-weighted MR images and hyperintense on T2-weighted and FLAIR images (Fig. 57.2). Gadolinium enhancement is present in 10% to 30% of cases, and if present is usually faint and patchy. Imaging alone does not clearly distinguish the histologic subtypes of LGG, though calcification is more common among oligodendrogliomas or oligoastrocytomas than among astrocytomas. Infiltration of tumor cells nearly always extends beyond the margins of radiographically visible tumor. Serial MRI scans show variable growth rates of LGG over time; some tumors, especially oligodendrogliomas, grow very slowly.

FIGURE 57.2 Axial MRI scan from a patient with a left temporal low-grade oligodendroglioma, showing no contrast enhancement on T1-weighted images (A) and diffuse hyperintensity on FLAIR images (B). FLAIR, fluid-attenuated inversion recovery; MRI, magnetic resonance imaging.

B.  Therapy.

Few of the key issues regarding treatment of patients with LGG have been studied in well-designed prospective or randomized clinical trials. It is therefore difficult to dogmatically state the “conventional” treatment for these tumors. The proper treatment for patients needs to be individualized and based on several factors, including patient age, clinical presentation, tumor size and location, tumor histology, and molecular genetic profile.

The fact that MRI identifies most patients with LGG early in their natural course raises the question of whether all patients require immediate treatment when the lesion is discovered. Currently the unequivocal indications for early intervention for patients with a presumed or proven LGG include neurologic signs and symptoms other than seizures; presence of significant mass effect on neuroimaging; growth of the lesion on serial scans; and patient age ≥50 years. It is unclear whether the presence of MRI contrast enhancement should be an indication of early treatment, assuming the area of enhancement is biopsied and shown to be histologically low-grade. For younger patients with presumed LGG who have no neurologic symptoms other than seizures, the recent trend has been to offer early surgery if aggressive resection can be done safely (see next paragraph). A reasonable alternative approach is to follow these patients closely with serial MRI scans, and defer treatment until clinical or radiographic tumor progression occurs.

Surgical resection of LGG is rarely curative. The potential goals of surgery are to relieve neurologic symptoms caused by mass effect, to improve seizure control, and to improve long-term survival. The impact of the extent of surgical resection on patients’ ultimate survival has never been studied prospectively in which “ideal candidates” with LGG were randomly assigned to undergo varying degrees of surgical resection. Patients who have extensive resection are more likely to be younger, have better performance status, and have small, unilateral, relatively well-circumscribed tumors in noncritical locations than patients who have more conservative surgery. These features are probably in themselves favorable prognostic factors. Several retrospective series indicate a survival advantage for LGG patients who underwent extensive surgical resection as compared with those who had only biopsy or “partial” tumor excision. Some studies suggest a lower risk of subsequent “malignant transformation” (see Section C) for patients with LGG who undergo a more extensive initial resection.

RT is generally recommended for patients with LGG who require treatment and who do not undergo aggressive surgical resection. There is uncertainty whether all patients with LGG should receive RT early in their course. In a large prospective multicenter study, patients with newly diagnosed LGG were randomized to either receive 54 Gy RT immediately after initial biopsy or resection, or to receive no RT until tumor progression. There was no difference in overall survival of patients who received early RT compared to patients in whom RT was deferred, though there was suggestion of delayed time to tumor progression in patients receiving early RT.

A major reason for not treating all patients with newly diagnosed LGG with early RT is concern over long-term neurocognitive toxicity of RT. This is a significant concern for patients with LGG, because at the time of initial diagnosis most patients are young, have mild or no neurologic deficits, and have an anticipated survival of at least several years. Recent evidence suggests worsening neurocognitive function as LGG patients are followed for many years after RT. The question of whether early RT is more likely to have a positive or a negative effect on patients’ long-term neurologic function and quality of life is still unanswered.

The role of chemotherapy for patients with LGG is in a state of evolution. A recent randomized study of patients with newly diagnosed “high-risk” LGG (i.e., patients over age 40 years, or undergoing less than a “complete” surgical resection) showed significantly prolonged progression-free survival and overall survival among patients who received postoperative RT plus PCV chemotherapy, versus patients randomized to surgery + RT and no chemotherapy. Whether the benefit of RT + chemotherapy applies to all patients with “high-risk” LGG or is restricted to certain molecular subgroups is not yet clear. Previous studies have shown better response to PCV or to temozolomide among low-grade oligodendrogliomas with chromosome 1p/19 codeletion. It is not known whether RT + PCV should be offered to all LGG patients, including those under age 40 or who undergo extensive initial resection. The relative efficacy of PCV versus temozolomide for LGG is unclear. Finally, it is not known whether a subset of patients could derive survival benefit from upfront chemotherapy only, rather than RT + chemotherapy, thus avoiding or at least deferring the risk of neurotoxicity of RT.

C.  Prognosis.

In recent series the median survival of adults with supratentorial grade 2 astrocytoma is 5 to 9 years, and with grade 2 oligodendroglioma 8 to 12 years. Patient age at diagnosis is a strong independent predictor of outcome: time to tumor progression and overall survival are significantly shorter for older patients, particularly those over 50 years of age. Significant neurologic impairment at diagnosis has a negative impact on survival. Patients who present with a long history of seizures and no other neurologic deficits have a relatively favorable prognosis. In some series, the presence of contrast enhancement on initial computed tomography (CT) or MRI scans was predictive of shorter survival. Larger pretreatment tumor size (>4 to 5 cm) is predictive of shorter survival. This at least partly reflects the greater difficulty in resecting larger tumors. It is also possible that larger tumors are inherently more aggressive.

At the time of tumor recurrence or progression, about 75% of initially grade 2 astrocytomas and about 50% of initially grade 2 oligodendrogliomas will have undergone “malignant transformation” to a grade 3 or grade 4 tumor. Malignant transformation of LGG tends to occur sooner and more frequently among older patients than in younger patients. This histologic and phenotypic transformation reflects the acquisition of several genetic abnormalities. Unfortunately, it is not rare for LGG that has remained stable for several years to eventually show progression leading to a fatal outcome. There does not seem to be a time point beyond which patients with LGG can be confidently declared to be “cured” of their tumor.

As discussed above, the IDH and chromosome 1p/19q status of LGGs has prognostic significance independent of histologic subtype. Unfortunately, several large recent studies of LGG were carried out and published before this information was recognized. Future advances in management of patients with LGG will certainly incorporate molecular profiling of patients’ tumors.

MENINGIOMA

A.  Course of disease.

Meningioma is the most common primary CNS tumor in adults. The majority of meningiomas are asymptomatic and discovered incidentally by neuroimaging studies or at autopsy (see Section B). Symptomatic meningiomas are twice as common among women than men and account for approximately 20% of primary brain tumors in adults. There is a steadily increasing incidence above 20 years of age, with peak incidence during the seventh decade.

The WHO classification uses hypercellularity, nuclear pleomorphism, mitotic rate, focal necrosis, and infiltration of brain parenchyma to divide meningiomas into “benign” (grade 1, accounting for 85% of cases), “atypical” (grade 2, 5% to 15% of cases), and “malignant” or “anaplastic” (grade 3, 1% to 5% of cases). There is a variety of histologic subtypes of meningiomas, including meningothelial, transitional, and fibrous; these subtypes generally do not have prognostic significance, except for more aggressive clinical behavior among the clear-cell, chordoid, rhabdoid, and papillary subtypes. Brain invasion is associated with a higher rate of tumor recurrence after therapy.

The clinical presentation of meningiomas is determined by their anatomic site. The most common sites of origin are along the cerebral convexity, parasagittal area and falx, and along the sphenoid ridge; together these sites account for at least two-thirds of cases. The slow growth of these tumors is reflected in the slow progression of signs and symptoms.

Meningiomas arise adjacent to dural surfaces and have a characteristic diffuse, homogeneous contrast enhancement on CT or MRI scans (Fig. 57.3). Calcification is present in at least one-third of cases. Peritumoral cerebral edema is variable and in some cases dramatic. Approximately 20% of patients have hyperostosis in the skull adjacent to the tumor; this bone is usually invaded by tumor cells. Approximately 5% of patients have two or more meningiomas at separate sites. The neuroimaging features of atypical or malignant meningiomas do not differ reliably from those of benign tumors. Arteriography or MR angiography/venography is frequently required to delineate the tumor’s blood supply in consideration of surgery or preoperative embolization.

FIGURE 57.3 Axial T1-weighted MRI scan from a patient with a right parasellar meningioma, showing homogeneous contrast enhancement extending into the adjacent cavernous sinus and orbit. MRI, magnetic resonance imaging.

B.  Therapy.

Modern neuroimaging techniques have led to increased detection of incidentally discovered, asymptomatic meningiomas. Serial MRI scans in these patients usually show slow or no growth over several years. It is reasonable to defer surgery or other interventions, especially in elderly patients, unless symptoms develop or the tumor clearly enlarges.

The optimum treatment for symptomatic meningiomas is total surgical resection, if it can be done safely. The success (and morbidity) of aggressive surgery depends mainly on tumor location. Overall, gross total resection can be achieved in approximately 75% of patients. Tumors along the hemispheric convexity, anterior falx, or olfactory groove are most amenable to complete excision. For meningiomas arising in some anatomic locations such as petroclival, parasellar, cavernous sinus, or orbital tumors, gross total resection is often not possible without causing unacceptable neurologic morbidity. Some patients with recurrent meningioma are candidates for a second surgical resection, depending on tumor size and location.

RT is not given following gross total resection of benign meningioma, but is generally recommended for patients with (1) symptomatic benign meningioma not amenable to aggressive surgical resection; (2) significant residual benign meningioma following attempted resection; (3) recurrent tumor following surgery; and (4) newly diagnosed atypical or anaplastic meningioma, regardless of the extent of initial surgical resection. Of these indications for RT, perhaps the most controversial is the group of patients with subtotally resected benign meningioma. The weight of retrospective data suggests a significantly lower long-term recurrence rate for these patients if they receive RT shortly after surgery, but it is common practice to defer RT and monitor serial MRI scans.

RT options for meningioma include “standard” fractionated conformal RT, intensity-modulated RT, single-dose or fractionated stereotactic radiosurgery, interstitial brachytherapy, and proton beam therapy. Intensity-modulated RT, stereotactic radiosurgery, and proton beam therapy offer the theoretical advantage of being able to deliver a therapeutic dose to an irregularly shaped target, with reduced risk to nearby normal structures such as the optic pathways or brainstem. Published series report partial tumor shrinkage in 30% to 50% of patients and “tumor control” (stable or improved MRI scans) in up to 90% of patients, at least over a 5-year follow-up period. There are only a few studies that have determined control rates over 10 years or longer. Despite the common occurrence of meningiomas, there are virtually no prospective or controlled studies comparing different RT modalities, or establishing optimal patient selection, RT doses, tumor target volumes, or fractionation schemes.

A significant proportion of patients with recurrent meningioma have tumors, which are not surgically resectable, have exhausted options for RT, and would therefore benefit from effective systemic treatment. Unfortunately, meningiomas are generally not sensitive to currently available chemotherapy agents. There are a few reports of partial response or prolonged tumor stabilization in patients with recurrent or anaplastic meningiomas treated with hydroxyurea, temozolomide, other chemotherapy regimens, tamoxifen, antiprogesterone agents, interferon-alpha, somatostatin, bevacizumab, or sunitinib. To date, molecularly targeted agents such as the tyrosine kinase inhibitors imatinib or erlotinib have not shown significant efficacy.

C.  Prognosis.

The most important prognostic factors for meningioma are the extent of initial resection and the histologic tumor grade. Following gross total resection of benign meningioma, recurrence-free survival rates are close to 90% at 5 years, declining to 75% at 10 years and 65% at 15 years. A high percentage of these patients never have tumor recurrence during their lifetime. Following subtotal resection alone, tumor recurrence rates at various time points are at least twice as high as for patients with gross total resection. Retrospective studies suggest improved outcome for patients who receive postoperative RT after incomplete resection.

Patients with atypical and malignant meningiomas clearly have a higher tumor recurrence rate and a shorter survival outlook than benign tumors. Approximately 50% of patients with atypical or malignant meningioma have tumor recurrence within 5 years of initial treatment. Reported median overall survival times vary between 2 and 10 years.

There are recent studies correlating molecular genetic changes in meningiomas with patient outcomes. For example, tumors with complex karyotypic abnormalities at diagnosis tend to behave more aggressively. Molecular profiling of meningiomas is not yet part of standard clinical practice.

PRIMARY CENTRAL NERVOUS SYSTEM LYMPHOMA

A.  Course of disease.

The great majority of primary CNS lymphomas (PCNSLs) occur sporadically in persons with no apparent immune deficiency. The peak incidence among immunocompetent persons occurs between age 60 and 65 years. Recent epidemiologic studies suggest an increasing incidence among older adults. PCNSL accounts for about 3% of all primary brain tumors in adults. PCNSL is disproportionately common among patients with HIV infection, though the incidence has dropped dramatically with the advent of modern antiretroviral therapy. PCNSL may also occur in recipients of organ transplants or in persons with other iatrogenic immunodeficiency states.

More than 90% of PCNSLs are classified as diffuse large-cell B-lymphocyte tumors. The Epstein–Barr virus is detected in 90% of PCNSLs associated with HIV infection or organ transplants, but only rarely in sporadically occurring tumors. The origin and pathophysiology of PCNSL in immunocompetent persons are poorly understood.

Patients generally present with a combination of altered mental status and focal neurologic symptoms. Neurologic deficits often progress rapidly and the diagnosis is usually made within 2 to 3 months. Seizures are less common than among patients with gliomas. PCNSL has a predilection for arising in deep or midline brain structures. On MRI scans PCNSL characteristically appears as a bright fairly homogeneously enhancing mass lesion (Fig. 57.4). About one-half of patients have multifocal lesions. Lymphomatous infiltration of the posterior vitreous and/or retina (often asymptomatic) occurs in 10% to 20% of patients. Leptomeningeal dissemination occurs at some time in 10% to 40% of patients and is usually asymptomatic when present at the time of initial diagnosis.

FIGURE 57.4 Coronal T1-weighted MRI scan from a patient with primary CNS lymphoma, showing a large area of bright homogeneously enhancing tumor centered in the left thalamus, and a smaller focus of enhancing tumor in the superficial right frontal lobe. CNS, central nervous system; MRI, magnetic resonance imaging.

B.  Therapy.

PCNSL is unique among primary brain tumors in that corticosteroids not only reduce peritumoral cerebral edema, but also have a direct oncolytic effect and can produce significant (but temporary) clinical and radiographic improvement. Whenever clinically possible, steroids should be withheld prior to biopsy of patients with suspected PCNSL because their oncolytic effect may render the biopsy nondiagnostic.

There is no definite evidence that attempted surgical resection provides a survival benefit for patients with PCNSL. The role of surgery for suspected PCNSL is to provide a histologic diagnosis.

Patients with newly diagnosed PCNSL should have a staging workup including MRI of the brain and total spine, cerebrospinal fluid (CSF) exam (if safe) for cytology and flow cytometry studies, slit lamp ophthalmologic exam, CT scans of the chest and abdomen, serum lactate dehydrogenase, and HIV serology. Immunoglobulin H gene rearrangement analysis of CSF may show evidence for leptomeningeal tumor when other studies are negative or equivocal. It is not clear whether all patients should have a bone marrow biopsy and/or total-body 18-fluoro-deoxyglucose positron emission tomography scan.

High-dose intravenous methotrexate is the mainstay of treatment for PCNSL. When given in sufficient doses methotrexate penetrates into the brain parenchyma regardless of the state of the blood–brain barrier, and also produces cytotoxic concentrations in the CSF. The optimal methotrexate dose, schedule, and number of treatment cycles are not clearly known. For patients treated with high-dose intravenous methotrexate, upfront intrathecal chemotherapy is generally not recommended in the absence of definite radiographic or CSF evidence for leptomeningeal tumor.

Rituximab is a monoclonal antibody against the CD20 B-lymphocyte cell-surface marker, and is cytolytic for B-cell lymphomas. Current regimens for newly diagnosed PCNSL generally combine rituximab with methotrexate. High-dose intravenous cytarabine also achieves good brain and CSF concentrations. Two cycles of cytarabine are commonly given as “consolidation therapy” following methotrexate and rituximab. There are numerous published studies of multiagent regimens in which other chemotherapy drugs, including temozolomide or procarbazine, are added to high-dose methotrexate, but no randomized comparative studies demonstrating a clear survival advantage.

Other chemotherapy options for newly diagnosed PCNSL include hyperosmolar disruption of the blood–brain barrier followed by a combination of intra-arterially and systemically administered drugs. In patients who achieve a complete radiographic response (no residual contrast-enhancing tumor) to initial methotrexate-based chemotherapy, subsequent high-dose chemotherapy with autologous stem-cell rescue may provide good overall survival outcomes. Most published series of this approach preselected patients for younger age and good performance status.

PCNSL is highly responsive to RT, but following RT alone the tumor recurs quickly and the median survival is only 12 to 18 months. Whole-brain RT (35 to 50 Gy) is generally given after the “induction” methotrexate-based chemotherapy. Whole-brain RT should be given to all patients who do not attain a complete radiographic remission following induction chemotherapy. It is less clear whether all patients who achieve a complete radiographic remission to initial methotrexate-based chemotherapy should then receive “consolidation” whole-brain RT. There are conflicting data whether consolidation RT necessarily extends overall survival in these patients, versus deferring RT until the time of tumor recurrence.

C.  Prognosis.

Younger age and good initial performance status are the two most important prognostic factors for survival outcome in PCNSL. The median survival of patients initially treated with methotrexate-based chemotherapy is 3 to 5 years. Overall survival is better among patients who achieve a complete remission to the initial chemotherapy regimen.

There is concern over delayed neurotoxicity of PCNSL treatment: the risk of severe neurocognitive decline and leukoencephalopathy in survivors increases with patient age and among patients who receive methotrexate plus RT, versus patients who receive chemotherapy only.

MEDULLOBLASTOMA

A.  Course of disease.

Medulloblastoma is the most common malignant brain tumor of childhood, comprising 20% of brain tumors occurring before age 18 years. There is a bimodal incidence peak, at 3 to 4 years and 8 to 10 years of age, with a slight male predominance. About 20% of all medulloblastomas occur in adults, usually before age 30 years.

The WHO classification divides medulloblastomas into three main histologic groups. At least two-thirds of tumors have a “classic” histology, with sheets of “small, round, blue” tumor cells with hyperchromatic nuclei. The nodular/desmoplastic histologic pattern is present in 10% to 20% of cases, and is disproportionately common in adults and in children under 3 years of age. The third histologic group shows severe anaplasia and/or large tumor cells, accounting for 5% to 20% of cases.

Medulloblastomas in children usually arise in or near the cerebellar vermis and fourth ventricle, and thus present with a combination of headache, vomiting (often occurring in the morning), lethargy, and gait ataxia. Tumors arising more laterally in the cerebellar hemisphere present with ipsilateral ataxia, with or without signs and symptoms of increased intracranial pressure. Tumor enlargement or invasion into the brainstem causes cranial nerve palsies and long-tract findings. The diagnosis is usually made within 2 to 3 months of symptom onset.

Medulloblastoma is the primary brain tumor most likely to disseminate in the subarachnoid space, and is also the brain tumor most likely to metastasize outside the CNS, usually in the setting of recurrent disease at the primary site.

On MRI scans medulloblastoma usually appears as a homogeneously or heterogeneously enhancing mass filling and distorting the fourth ventricle. The tumor may be centered more laterally in the cerebellar hemisphere (Fig. 57.5). Calcifications or hemorrhage may be present. Hydrocephalus is present in at least 75% of cases at diagnosis. At initial diagnosis all patients should have total spine MRI and CSF exam to look for leptomeningeal tumor dissemination, present in about 25% of patients.

B.  Therapy.

Multimodality treatment for medulloblastoma includes aggressive surgical resection, followed by “risk-adapted” RT and chemotherapy. Gross total resection can be performed in approximately 75% of patients. One-half of patients require placement of a permanent CSF shunt. Postoperatively, children are clinically stratified into “average-risk” and “high-risk” prognostic subgroups based on the extent of initial surgical resection and the presence or absence of leptomeningeal dissemination. Average-risk patients (about two-thirds of the total) have a gross total or nearly gross total tumor resection, negative CSF cytology, and no leptomeningeal spread on brain and total spine MRI scans. Patients are designated high-risk if they have a less complete tumor resection, and/or evidence for leptomeningeal dissemination at diagnosis.

FIGURE 57.5 Coronal contrast-enhanced T1-weighted MRI scan from a young man with a desmoplastic medulloblastoma in the left cerebellar hemisphere. MRI, magnetic resonance imaging.

Average-risk children older than 3 years of age receive RT to the craniospinal axis (23 to 25 Gy), plus a higher RT dose to the tumor site (55 Gy) and posterior fossa (36 Gy). Proton beam RT reduces toxicity to nearby non-neural organs. Multiagent chemotherapy (usually including cisplatin, cyclophosphamide, and vincristine) is given for several months after RT.

Children over age 3 years with high-risk disease also receive postoperative RT, usually at a higher craniospinal axis dose than average-risk patients. There is a general strategy to give more intensified chemotherapy regimens to high-risk than to average-risk children, though there is no clear evidence establishing the best approach.

Children younger than 3 years of age have a higher incidence of leptomeningeal dissemination at diagnosis. The risk of severe neurocognitive toxicity in survivors is much higher if RT is given early in childhood, so these patients generally receive intensive chemotherapy regimens after surgery with the goal of avoiding or at least deferring RT for as long as possible.

Following tumor resection, adults with medulloblastoma are stratified into average-risk and high-risk groups as are older children, and treated with RT and chemotherapy accordingly. Adults tend to tolerate the multiagent “childhood medulloblastoma” chemotherapy regimens less well than do children.

Recent identification of key molecular signaling pathways in medulloblastoma and the recognition of different molecular subgroups (see Section C) are gradually leading to trials of molecular targeted therapies. In the future these therapies will hopefully provide more individualized approaches to increase efficacy and reduce toxicity.

C.  Prognosis.

The most frequent mode of treatment failure for medulloblastoma is recurrence in the posterior fossa, with or without leptomeningeal dissemination. In modern series that include chemotherapy as part of multimodality treatment, the 5-year progression-free survival rate for older children with average-risk disease is 80% to 90%. The majority of these children are cured. The 5-year progression-free survival rate is 50% to 60% for older children with high-risk disease, and 30% to 50% for children younger than 3 years of age. Large-cell/anaplastic medulloblastomas generally carry a worse outcome. The nodular/desmoplastic variant in young children is associated with better survival outcome. Metastatic disease at diagnosis carries a worse prognosis at any age. The present clinical staging scheme is not able to identify which average-risk patients are more likely to develop tumor recurrence and therefore require more aggressive initial treatment, nor to identify which patients could be cured with less aggressive treatment (especially the dose of craniospinal RT) so as to reduce the incidence and severity of long-term treatment sequelae.

Recent gene expression profiling studies divide medulloblastomas into four major subgroups with differing molecular genetics and somewhat different (though overlapping) representation of patient age, gender, tumor histology, and clinical outcomes. These groups are designated SHH (characterized by activation of sonic hedgehog or SHH pathway signaling), Wnt (featuring upregulation of Wnt pathway signaling), Group 3, and Group 4. Patients in the Wnt subtype (about 10% of the total) have the best clinical outcome, whereas Group 3 patients have the least favorable outcome. Infants in the SHH group (usually desmoplastic or nodular tumors) actually have excellent outcomes even without RT. Most adult medulloblastomas are in the SHH subtype, though with a different gene expression profile from infants. It is hoped that molecular subtyping will further refine the current clinical patient staging and help to individualize therapy.

The relatively favorable survival outcome and potential curability of medulloblastoma are tempered by significant treatment sequelae in the majority of survivors. About 25% of children develop the “cerebellar mutism syndrome” within a few days after surgery. This consists of mutism, axial hypotonia, ataxia, and irritability. Patients eventually recover, but one-half of severely affected children have long-term speech, motor, and cognitive deficits. Survivors of childhood medulloblastoma have a high incidence of other long-term sequelae, including growth failure and other neuroendocrine dysfunction, hearing loss, neurocognitive deficits that may be progressive, requirement for special education, behavioral disorders, cerebrovascular disease, and the risk of second neoplasms including meningioma and glioma. Toxicities are more common and more severe among children treated at a younger age.

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