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NEUROSURGERY
General principles of Neurosurgery
Surgical management of CNS tumors differs in many respects from general oncosurgery principles.
- En bloc resections are the norm in oncosurgical practice.
However such radical resections may not always be possible in CNS tumors. The brain and spinal cord are highly eloquent areas, where the risk of neurological deficits at the slightest insult is high. Most intra-axial tumors do not have a discrete plane of demarcation from normal parenchyma. Even where it does exist there may be admixed normal tissue, precluding a radical excision. Safe maximal resection remains the underlying tenet. Recent technological advances facilitate maximization of the extent of resection without compromising the safety.
- The surgical access through the rigid bony skull is limited, often necessitating working through narrow corridors. Deep seated lesions further require traversing normal tissue to reach the site of the tumor. The normal parenchyma’s low threshold to withstand mechanical pressure necessitates minimization of retraction. The safest route to a given lesion needs to be individualized based on a thorough preoperative assessment of imaging combined with sound knowledge of microsurgical anatomy.
- Obstruction of CSF pathways with resultant hydrocephalus is a very important issue, especially for tumors of the posterior fossa. The proximity of these tumors to the fourth ventricle and subsequent obstruction of cerebrospinal fluid (CSF) circulation results in hydrocephalus commonly. Variable degrees of hydrocephalus are thus a common presenting feature of posterior fossa tumors, occurring in almost 80% of cases. However not all patients may be symptomatic for the hydrocephalus. In addition, in a proportion of patients, direct removal of tumor may relieve the hydrocephalus.
Goals of Surgery
The aim of surgery is threefold:
- Achieving cure (where feasible viz. certain extra-axial tumors like meningiomas, acoustic neuromas, and some benign intra-axial lesions like hemangioblastomas, pilocytic astrocytomas) or maximal safe resection otherwise in an effort to improve the prognosis.
- Establishment of histological diagnosis. Sampling of larger amount of tissue allows a more confident histological assessment of tumor type and grade.
- Symptomatic relief from effects of local/generalized raised pressure and/or CSF obstruction.
Technical adjuncts to Surgery
- Microscope: Use of an operating microscope is become routine. It affords improved illumination, magnification and stereoscopic view at a depth, enhancing the view and facilitating performance of more radical and complex surgeries safely.
- Adjuncts to tumor localization and margin delineation
- Stereotactic localization : Use of frame based and frameless stereotactic devices (neuronavigation/image guided surgery) allow for accurate localization and delineation of tumor extent . Intraoperative brain-shift due to decompression and CSF drainage intraoperatively limit the accuracy of this technique.
- Intraoperative imaging : Intraoperative MR allows exact delineation of tumor extent, eliminating the problems with brain shift. This technology is however prohibitively expensive and not available freely. A more easily available option is the use of intraoperative ultrasound , a technology which is highly underutilized.
- Neuro-endoscopy is fast gaining favour as a means of minimally invasive approach to a host of regions especially intraventricular and skull base.
- Intraoperative electrophysiological monitoring of cortical activity as well as cranial nerves allows prediction of and prevention of neural injry.
- Awake craniotomy supercedes all the other technologies in allowing realtime monitoring of neurological function intraoperatively.
- Adjuncts to tumor debulking – facilitate easy and safe debulking of tumor
- Mechanical methods such as suction (for soft tumors), ultrasonic aspiration (for firmer tumors)
- Physical methods such as laser and cryo therapy in select cases.
Stereotactic biopsy (STB)
Stereotactic biopsy involves tissue sampling from within the brain using specially designed frames coupled to imaging systems (CT and/or MR) which guide the site of biopsy. Morbidity mainly consists of the risk of hematoma formation which is in the vicinity of 3%. The drawback of a limited biopsy is of course the lack of global sampling, which may be of concern in a heterogeneous lesion such as a glioma, where the biopsied site may not be representative of the entire lesion. Hence, the obvious benefits of a minimally invasive procedure such as stereotactic biopsy need to be weighed carefully against the potential drawbacks.
STB is indicated in
- Lesions where the diagnosis of a tumor is suspect and only a diagnostic tissue is required e.g lymphoma, infective/inflammatory, demyelinating pathology.
- Tumors which are not amenable to open surgery
a. Deep seated
b. Small lesions
c. Close to eloquent cortex
CSF diversion
Hydrocephalus is a common presenting feature in a large majority of primary brain tumors. In the vast majority, it is relieved by debulking surgery. In spite of this there remains a subset of patients who would require a procedure for CSF diversion at some point of time. The indication for CSF diversion and its timing with respect to the tumor surgery remain controversial. Shunt malfunction and mechanical complications at the abdominal end warrants judicious use of this procedure.
Not all patients however will require a shunt upfront. Almost 2/3rds to 3/4ths can be managed with temporary CSF drainage alone (ventricular tap, EVD). However there remains a subgroup who do require it either preoperatively (ideally) or subsequently when a complication arises or hydrocephalus increases despite tumor removal. Various studies have attempted to study various predictive factors that would help in selecting patients for shunt placement. However these studies are uniformly hampered by the retrospective nature of such analyses.
Based on available evidence a rationale management algorithm would be:
RADIOTHERAPY
General principles of radiotherapy
Radiotherapy is an integral component of the multimodality management of primary brain tumors with potential impact upon local control, symptom improvement, and progression free survival for low-grade and benign neoplasms and also overall survival for malignant brain tumors. Following maximal safe resection, adjuvant radiotherapy is indicated for all high-grade primary brain tumors in the postoperative setting. For completely excised benign tumors, such as pituitary adenomas and benign meningiomas, currently there is no role of upfront adjuvant radiotherapy. For low grade gliomas too, with no residual tumor on neuroimaging, surveillance alone is a reasonable option. However radiotherapy is recommended in such tumors either if a macroscopic residual tumor is evident on postoperative imaging or if tumor progression is documented on serial imaging. For tumors in the eloquent cortex where only a partial excision or biopsy if possible, radical radiotherapy is needed to improve outcome.
Radiotherapy planning:
Positioning & Immobilisation: Supine position with appropriate neck flexion (neutral for high fronto-parietal and maximal flexion for temporal lobe neoplasms or sellar/parasellar lesions) is the preferred position for most primary brain tumors excepting craniospinal irradiation where prone position on a specialized head-support device is preferred. Customised immobilization is recommended with thermoplastic face mask. Radiotherapy portals can be marked on the mask taking help from the diagnostic imaging. For 3-D planning, a contrast CT scan with thin slices through the region of interest and beyond is needed in the treatment position with the immobilization device. For high-precision techniques, a relocatable stereotactic frame or a customized sterotactic head-mask should be prepared, and a planning MRI scan should also be considered for CT/MRI fusion for better delineation.
Volume delineation: Gross tumour volume (GTV) comprises of contrast enhancing tumor on preoperative CT/MRI for all high-grade tumors and any residual visible tumour on the post-operative planning images for benign and low grade tumors. Clinical Target Volume (CTV) that encompasses any subclinical microscopic extension is variable depending upon the infiltrating nature of the tumor. Generally, it is 2cm margin to the GTV for high-grade tumors, 0.5-1cm for low grade, and 0.5 cm for benign tumors, which is edited where no spread is possible (e.g. intact bone, tentorium). Planning Target Volume (PTV) is generated 3-dimensionally over CTV to account for set-up errors in daily reproducibility and should ideally be generated in each department individually. For brain, a PTV margin of 5 mm seems safe for routine treatment. For conformal treatments with facility for serial verification, it can be further reduced to 3 mm and should be in the range of 2-3 mm for fractionated stereotactic radiotherapy depending upon equipment specification and tolerance. Critical structures such as optic chiasm, optic nerves, temporal lobes, brainstem, eyes and lenses, normal brain, cochlea, pituitary hypothalamic axis, etc should be drawn and doses to these structures also calculated to compare different plans.
Field arrangement: For simulated patients, either a 2-field or 3-field arrangement with appropriate wedges is the norm. In case of CT planning, conventional beam arrangement can be substituted with non-coplanar techniques for improving conformity. For stereotactic treatments, 6-9 field non coplanar arrangement gives the most optimal dose distribution.
CHEMOTHERAPY
Principles of chemotherapy and biological therapy
The role of chemotherapy and biological therapy in the multidisciplinary management of primary brain tumors continues to evolve rapidly. The goal of chemotherapy is to kill tumor cells directly by making them unable to replicate or to enhance normal process of cell death - apoptosis. Chemotherapy drugs may be cytotoxic or cytostatic. Some chemotherapy drugs act during specific parts of the cell cycle (cell-cycle specific drugs). Other drugs are effective at any time during the cell cycle and are referred to as non cell-cycle specific drugs. Combining non cross-resistant drugs to improve efficacy and reduce toxicity is the basis of contemporary multi-agent chemotherapy regimens.
Cytotoxic agents for primary brain tumors
Alkylating agents act by forming a molecular bond which prevents them from reproducing: Cisplatin, carboplatin, cyclo-phosphamide, temozolomide
Antimetabolites stop tumor cells from making the enzymes needed for new cell growth:
Methotrexate
Anti-tumor antibiotics stop the action of enzymes needed for cell growth: Rapamycin
Mitotic inhibitors usually disrupt microtubule assembly and interfere with the production of proteins: Etoposide (VP-16) and vincristine
Nitrosoureas stop tumor cells from repairing themselves: Carmustine (BCNU), and lomustine (CCNU).
Miscellaneous: Procarbazine
Cytostatic agents used for primary brain tumors
Reducing drug resistance: O6-benzylguanine (O6-BG)
Angiogenesis inhibitors: Thalidomide, interferon, CC-5013, COL-3, PTK-787, and suramins, bevacizumab
Growth factor inhibitors: Tyrosine kinase inhibitors such as imatinib; and epidermal growth factor receptor antagonists such as geftinib and erlotinib; and monoclonal antibodies such as nimutuzumab.
There are tremendous difficulties and challenges in treating primary brain tumors with systemic chemotherapy. The brain has a natural defense mechanism called the blood brain barrier, which protects the brain by acting as a filter. For a drug to be effective in treating these brain tumors, a sufficient quantity must either pass through the blood brain barrier or bypass it entirely. Blood brain barrier disruption is a technique used to temporarily disrupt this barrier in order to allow chemotherapy to flow into the brain. During blood brain barrier disruption, high osmotic agents such as mannitol are used to temporarily open the barrier. Very high doses of chemotherapy drugs are then injected systemically, which passes through the blood brain barrier into the tumor area. The barrier is restored naturally as the effects of the osmotic agent wanes.
One of the newer methods of delivering drugs to a tumor is convection enhanced delivery (CED). CED uses the principles of constant pressure to flow or infuse substances through brain tumor tissue. The procedure begins with surgery, during which a catheter (or multiple catheters, depending on the tumor size) is placed into the tumor area. The neurosurgeon then connects a pump-like device to the catheter, filling it with the therapeutic substance to be delivered to the tumor. The fluid flows, by use of pressure and gravity, through the tumor tissue. This convective-delivery method bypasses the blood brain barrier, placing the therapeutic substance in direct contact with tumor tissue. Receptor-mediated permeabilizers offer another way of delivering drugs through the blood brain barrier. They are laboratory created, but modeled after natural substances which temporarily increase the openings of the blood brain barrier, allowing drugs to pass into the brain.
Chemotherapy can also be delivered directly into the cerebrospinal fluid (CSF). This treatment is used for meningeal tumors involving the ventricles or spine, and tumors that tend to seed or spread, through the CSF. A small container system, such as an Ommaya Reservoir, is surgically placed under the scalp. A tube leads from the reservoir into a ventricle of the brain. Medications are injected via syringe into the reservoir and then the reservoir is pumped. The pumping begins the flow of drug through the ventricles and lining of the spine.
High grade glioma
High-grade gliomas (WHO grades III & IV) arise from malignant transformation of glial precursor cells and include anaplastic astrocytomas (AA), glioblastoma multiforme (GBM), anaplastic oligodendroglioma (AODG) and anaplastic ependymoma (AE). They are characterized as cellular tumors with poorly differentiated, round, or pleomorphic cells, occasional multinucleated cells, nuclear atypia, and anaplasia. Glioblastoma is the commonest and most aggressive of these glial tumors accounting for 50% of primary brain tumors. The presence of necrosis differentiates GBM from AA. Primary GBMs arise de novo and account for the vast majority of cases (60%) in adults over 50 years, with a short clinical history. Secondary GBMs (40%) typically develop in younger patients (<45 years) through malignant progression from a low-grade astrocytoma (WHO grade II) or anaplastic astrocytoma (WHO grade III). The time required for this progression varies considerably, ranging from less than 1 year to more than 10 years, the mean interval being 4-5 years. Increasing evidence indicates that primary and secondary glioblastomas constitute distinct disease entities that evolve through different genetic pathways, affect patients at different ages, and differ in response to some of the present therapies. Some of the more common genetic abnormalities are described as follows:
- Loss of heterozygosity (LOH): LOH on chromosome arm 10q is the most frequent gene alteration for both primary and
secondary glioblastomas, occurring in 60-90% of cases.
- p53: Deletion or alteration of the p53 gene appears to be present in approximately 25-40% of all GBMs.
- Epidermal growth factor receptor (EGFR) gene: Multiple genetic mutations are apparent, including both overexpression of the receptor as well as rearrangements that result in truncated isoforms.
- MDM2: Overexpression of MDM2 is the second most common gene mutation in GBMs and is observed in 10-15%
of patients.
- Platelet-derived growth factor–alpha (PDGF-alpha) gene: Amplification or overexpression of PDGFR is typical (60%)
in the pathway leading to secondary glioblastomas.
- PTEN: PTEN mutations have been found in as many as 30% of glioblastomas.
High-grade gliomas produce symptoms by a combination of focal neurological deficits from compression and infiltration of the surrounding brain, vascular compromise, and raised intracranial pressure. Presenting features include headaches (30-50%), seizures (30-60%) which may be simple partial, complex partial, or generalized, focal neurological deficits (40-60%), and mental status or personality changes (20-40%). Morbidity occurs from Proposed pragmatic prognostic classification for high-grade gliomas The treatment of malignant gliomas specially glioblastoma remains difficult with high morbidity and mortality and
| Favourable-prognosis HGG |
Poor-prognosis HGG |
| <50 years and independent* or semi-dependent (NPS 0-2) |
<50 years and dependent† (NPS 3-4) |
| > 50 years and independent (NPS 0-1) |
> 50 years and semi-dependent or dependent (NPS 2-4) |
* Patients who are independent (NPS 0,1) are considered as favourable prognosis. irrespective of age.
† Patients who are dependent(NPS 3,4) are considered as poor prognosis, irrespective of age. Patients who are semi-dependent (NPS 2) are considered as favourable prognosis if <50 years and poor prognosis if > 50 years of |
encompasses surgery, radiotherapy, and chemotherapy. The goals of surgery are to establish a pathological diagnosis, relieve mass effect, and, if possible, achieve a gross total resection to facilitate adjuvant therapy. Despite significant advances in neuroimaging, neurosurgery, radiotherapy and chemotherapy, the prognosis for high-grade gliomas has not changed much over the decades. The 5-year survival of anaplastic astrocytomas following maximal safe resection and adjuvant therapy is in the range of 35-50% with a median survival of 3 years. Historically there have been virtually no long-term survivors (5-year survival <3%) in GBM, with a 2-year survival <10% and median survival around 12 months. Only recently has addition of temozolomide in the concurrent and adjuvant setting to radical radiotherapy for newly diagnosed supratentorial glioblastomas shown to improve outcome with a 2-year survival of 25-30% and a median survival of 15 months, thereby becoming the contemporary standard of care. Based on predictive modeling, a nomogram is now available to predict the 2-year and median survival for glioblastoma treated with radiotherapy and temozolomide.
In children, the role of chemotherapy for treatment of high-grade glioma is still being defined and data suggests that the benefit from addition of chemotherapy, when compared to surgery and radiation therapy alone, is modest at best. As a result of the poor outcome for children with most high-grade gliomas, numerous single-agent phase II studies have been conducted using a variety of agents, including cisplatin, carboplatin, CCNU, procarbazine, cyclophosphamide, ifosfamide, etoposide, topotecan, temozolomide, and irinotecan. The data for CCNU and cyclophosphamide have shown the most promise. Despite the absence of solid evidence to support its use, chemotherapy is routinely used to treat children with supratentorial high grade astrocytomas. In the first phase III pediatric study, patients were randomly assigned to receive either local RT alone or local RT with weekly vincristine, followed by 1 year of carmustine, vincristine, and prednisone therapy (PCV). The 5-years EFS rates were 18% for the RT only group and 46% for those receiving chemotherapy. That study demonstrated a statistically significant better outcome for patients with GBMs but the number of patients with AAs was too small to show any meaningful difference in outcome. However, in the next large phase III study by Finlay et al., which randomized patients to receive adjuvant chemotherapy with 8-in-1 or PCV; no difference was observed between the two chemotherapy arms. Similarly, a few other phase II studies of a variety of chemotherapeutic regimens in the neoadjuvant and adjuvant setting including addition of six cycles of temozolomide after radiotherapy failed to show benefit of adjuvant chemotherapy.
Non-brainstem high-grade gliomas in infants and young children may behave completely differently to similar tumours in older children and adolescents. Indeed, a recent report of the French Society of Paediatric Oncology explored a chemotherapy-only strategy in this population. Five-year overall survival of this cohort was 59% and at the last follow-up visit, 55% children were alive (most without irradiation). These results are consistent with other reports in infants and young children. As a result, it is reasonable to treat these young children with alternative protocols that avoid irradiation as first line therapy in selected cases (patient younger than 2 years, grade III tumours, radiologically complete resection).
Probably the most important part of the management of patients with GBM is compassionate and effective supportive care. This care includes treatment of cerebral edema with a potent glucocorticosteroid (dexamethasone) which often requires prophylactic use of H-2 blockers to prevent gastrointestinal side effects; seizures prophylaxis and therapy with a modern anticonvulsant; and rehabilitative care as physical, occupational, speech therapy, and emotional and psychological support.
Low Grade Glioma
Low-grade gliomas (LGG) are a heterogeneous group of intrinsic CNS neoplasms that share certain similarities in clinical presentation, radiologic appearance, prognosis, and treatment. Low-grade gliomas arise from the neoplastic transformation of the supporting cells of the brain, the neuroglia. They are graded by the WHO system with the typical infiltrating fibrillary astrocytoma being graded as grade II. A subset of low-grade astrocytomas preclude the use of the usual 4-featured grading system. This subset may have endothelial proliferation and marked atypia; nevertheless, they are slow growing and well circumscribed and comprise juvenile pilocytic astrocytoma (JPA) and its variant a juvenile pilomyxoid astrocytoma, pleomorphic xanthoastrocytoma (PXA), and subependymal giant-cell astrocytoma (SGCA). Low-grade astrocytomas generally cause symptoms by perturbing cerebral function (eg, seizures), elevating intracranial pressure by either mass effect or obstructing cerebrospinal fluid (CSF) pathways (ie, hydrocephalus), or causing neurologic (and sometimes endocrine) abnormalities (eg, paralysis, sensory deficits, aberrant behavior, headaches). Infiltrating low-grade astrocytomas tend to occur in the lobes of the cerebral hemispheres, especially in the frontal lobe. Pilocytic astrocytomas may occur in the frontal, temporal, and parietal lobes and cerebellum, but they are also common in locations closer to the midline, such as the hypothalamus, thalamus, optic chiasm, and brain stem. In children, pilocytic astrocytomas have a predilection for the mesial structures of the cerebellum. PXAs also are found most commonly in the hemispheres, particularly the temporal lobes. SGCAs are found most commonly in the lateral wall of the third ventricle and almost exclusively in patients with tuberous sclerosis.
Histology including grade, age, performance status, seizures, neurological deficits, extent of resection, and use of radiotherapy have been variably associated with outcome. Pignatti’s criteria often help in determining prognosis and aid in decision making for adjuvant therapy. Factors associated with a worse outcome include age >40 years; lesion >6cm; midline shift; presence of neurodeficits; astrocytic rather than oligodendroglial histology; and high-MIB index.
Differences in patient populations, diagnostic methods, treatment guidelines, and reporting make defining the exact median survival duration for all patients with low-grade gliomas difficult. However, the median survival duration of patients with low-grade astrocytomas is approximately 7.5 years. The 5-year survival rates range from 65-80%, while the 10-year survival rates vary from 20-45%.
Over time, these tumors frequently undergo dedifferentiation into higher-grade lesions. Such lesions then grow more rapidly and eventually become fatal. Progressive neurologic deficit is the norm as the tumor increases in size. Even lesions that do not dedifferentiate but continue to grow can cause death ultimately, primarily as a result of mass effect that may result in cerebral herniation and brainstem dysfunction.
In children, surgery with or with out radiotherapy is the primary therapy for hemispheric low grade glioma. Chemotherapy plays an important role for children in whom either aggressive surgery or radiation therapy is inadvisable. These include; when aggressive primary or secondary surgery may be unsafe for tumors in deep locations or eloquent structures; in young children in whom a delay in radiation therapy may be desirable or for children whose tumor has progressed after irradiation. The response rates are modest and the usual benefit of chemotherapy is disease stabilization, although partial responses may occur. Complete tumor regression is rare, and progressive disease occurs in a subset of patients in many series. Common chemotherapy regimens include classic and/or nonclassic alkylators, nitrosoureas, and/or platinum analogues. Carboplatin and vincristine is the preferred first line regimen. In the seminal CCG study of 73 children with this regimen in newly diagnosed, progressive LGAs that were primarily diencephalic; radiographic responses were seen in 56% of patients and the 3-year PFS rates were 68%. Children 5 years old and younger had a significantly higher rate of 3-year PFS (74%) as compared with children older than 5 (39%; p < .01). Similarly, another effective regimen consisting of 6-thioguanine, procarbazine, dibromodulcitol, CCNU, and vincristine results in tumor reduction in 36% of patients, stable disease in 59%, and a 5-year survival of 78%. These two regimens form the basis of an ongoing randomized study within the COG, A9952, for patients with progressive LGA. The introduction of temozolomide allowed better response, including 24% CR and 37% PR rates (in children and adults) in a phase II study. An Italian study using Cisplatin and Etoposide resulted in a good 3 year PFS of 78 % and an overall survival of 100 %. In young children with optic glioma; regimen of vincristine and actinomycin-D allows 62.5% of the patients to remain free of progressive disease and radiation therapy at 4 years and 30% at 7 years. In the same group, Carboplatin alone produces improvement or stable disease in 78% patients. Currently ongoing trials in low grade glioma explore the following concepts: intensifying induction chemotherapy with etoposide (SIOP LGG 2004, TMH study), replacing vincristine by vinblastine to decrease the rate of peripheral neuropathy and combining temozolomide with the classical chemotherapy backbone (COG strategies).
Oligodendroglioma
Oligodendrogliomas (ODG) are primary glial brain tumors that arise from oligodendrocytes and are divided into grade II and anaplastic grade III tumors (WHO). Typically, they have an indolent course, and patients may survive for many years after symptom onset. Oligodendrogliomas may be diagnosed at any age but occur most commonly in young and middle-aged adults, with a median age at diagnosis of 40-50 years. In children, only 6% of gliomas are diagnosed as oligodendrogliomas. Like other intracranial space-occupying lesions, oligodendrogliomas present with focal cerebral dysfunction, depending on location, and rarely as increased intracranial pressure. Typically, they are cortical or subcortical; they rarely are found in deep gray structures, and occasionally they may be primarily intraventricular. The most common presenting symptom is a seizure, observed at diagnosis in 50% of patients. Over 80% of patients experience seizures at some time during their illness, which can be simple partial, complex partial, or generalized, depending on the location of the tumor. Tumors that arise within the ventricles may cause obstructive hydrocephalus and are more likely to disseminate through the cerebrospinal fluid (CSF). Rarely, they can metastasize outside the nervous system.
Their good prognosis relative to other parenchymal tumors probably stems from inherently less aggressive biological behavior and a favorable response to chemotherapy based on genetic characteristics. Combined loss of 1p/19q is a significant predictor of overall survival and is also significantly associated with longer recurrence-free survival and chemosensitivity. Other variables, including age, location, extent of surgical resection, postoperative performance status, histologic features of the tumor, and use of adjuvant therapies, and seizures determine prognosis. The median survival from initial diagnosis of all low-grade oligodendrogliomas (LGOs) is 4-10 years, but it is only 3-4 years for anaplastic oligodendrogliomas. Patients with anaplastic oligodendrogliomas who have loss of heterozygosity on 1p and/or 19q live substantially longer (mean, 10 years) than patients whose tumors lack these genetic changes (mean, 2 years).
Ependymoma
Ependymomas are glial tumors that arise from ependymal cells within the CNS. The WHO classification scheme for these tumors includes 4 divisions based on histologic appearance: grade I (myxopapillary ependymoma and subependymoma); grade II (cellular, papillary, and clear cell variants); grade III (anaplastic ependymoma); and grade IV (ependymoblastoma). Myxopapillary ependymomas are considered a biologically and morphologically distinct variant of ependymoma, occurring almost exclusively in the region of the cauda equina and behaving in a more benign fashion than grade II ependymoma. Subependymomas are uncommon lesions that share the benign features of myxopapillary ependymomas.
Intracranial ependymomas present as intraventricular masses with frequent extension into the subarachnoid space, while spinal ependymomas present as intramedullary masses arising from the central canal or exophytic masses at the conus and cauda equina. In children, approximately 90% of ependymomas are intracranial, with the majority of these usually arising from the roof of the fourth ventricle (infratentorial). In adults and adolescents, 75% of ependymomas arise within the spinal canal, with a significant minority occurring intracranially in the supratentorial compartment. Intracranial ependymomas represent 6-9% of primary CNS neoplasms and account for 30% of primary CNS neoplasms in children younger than 3 years. They generally present in young children with a mean age of diagnosis of 4 years. Spinal ependymomas are most common in patients aged 15-40, most of which are of myxopapillary subtype.
Supratentorial ependymomas may be associated with increased intracranial pressure manifested as headache, nausea, vomiting, and cognitive impairment. Headaches can vary in intensity and quality and are frequently more severe in the early morning or upon first awakening. Changes in personality, mood, and concentration can be early indicators or may be the only abnormalities observed. Seizures are a presenting symptom in 20% of patients, and focal neurologic deficits may also be prominent. Spinal ependymomas usually are associated with a history of progressive neurologic deficit related to involvement of ascending or descending nerve tracts, exiting peripheral nerves, and pain that correlates with the level of the lesion. Dissemination of the tumor through the cerebrospinal fluid (CSF) is observed in <10% of patients at diagnosis, most of which are infratentorial.
The presenting symptom of tumors that involve the conus or cauda equina is pain in the back, rectal area, or both lower legs, often leading to a misdiagnosis of sciatica. Although the two regions are related anatomically, several clinical features can serve to distinguish lesions of the conus from those of the cauda equina.
Depending on the patient population, the reported 5-year overall survival rate for ependymoma varies from 45-65%.
Brainstem Glioma
Brainstem gliomas are tumors that occur in the region of the brain referred to as the brain stem, which is the area between the aqueduct of Sylvius and the fourth ventricle. The commonly used classification divides them into 4 distinct anatomic locations - diffuse intrinsic pontine, tectal, cervicomedullary, and dorsal exophytic types. Tumors also are characterized on the basis of site of origin, focality, direction and extent of tumor growth, degree of brainstem enlargement, degree of exophytic growth, and presence or absence of cysts, necrosis, hemorrhage, and hydrocephalus. Brainstem gliomas are highly aggressive brain tumors. Anatomic location determines the pathophysiological manifestation of the tumor. With tectal lesions, hydrocephalus may occur as a result of fourth ventricular compression. With pontine and cervicomedullary lesions, cranial nerve or long tract signs are observed commonly. They constitute 2-3% of all intracranial tumors in adults and 10-15% of intracranial tumors in children. Brainstem gliomas account for approximately 10-20% of all childhood brain tumors.
Common presenting symptoms include double vision, weakness, unsteady gait, difficulty in swallowing, dysarthria, headache, drowsiness, nausea, and vomiting. Rarely, behavioral changes or seizures may be seen in children. Older children may have deterioration of handwriting and speech. Common clinical findings can be summarized as constituting a triad of cranial nerve deficits, long tract signs, and ataxia (of trunk and limbs). Tectal lesions may present with diplopia reflecting an internuclear ophthalmoplegia, indicating involvement of the medial longitudinal fasciculus. Parinaud syndrome also may be seen, with paralysis of upward gaze and accommodation, light-near dissociation (loss of pupillary reflex to light with preservation of pupilloconstriction in response to convergence), eyelid retraction, and convergence-retraction nystagmus. Cervicomedullary lesions may present with sensory loss of the face (involvement of the trigeminal nucleus), dysphagia and/or dysphonia from lower cranial nerve involvement (commonly IX and X), long tract signs, and ataxia. Downbeating nystagmus and oculomyoclonus often are seen with medullary involvement. Patients with hydrocephalus may require ventriculostomy or ventriculoperitoneal shunting for symptomatic relief. Sudden death can result from increased intracranial pressure and subsequent cerebral herniation
Surgery is most appropriate in tumors of the cervicomedullary junction, dorsal exophytic tumors protruding into the fourth ventricle, cystic tumors, enhancing tumors with clear margins that exert a space-occupying effect, and finally, benign tumors (ie, those with slow clinical progression). Typically, biopsy and/or surgery are not required for diagnosis or treatment of diffuse intrinsic pontine or tectal gliomas and cannot be recommended routinely; diagnosis can be made clinico-radiologically alone. Focal radiotherapy is the cornerstone of treatment of brainstem gliomas and should be administered to any patient with significant and progressive neurologic symptoms. Some adult patients with a tectal or cervicomedullary lesion, or with mild symptoms of long duration, may be candidates for observation alone; radiotherapy can be reserved for patients with clear evidence of tumor progression.
Pontine tumors are the most common variety of brainstem tumor. They also carry the worst prognosis; in children, the median survival duration is 9-12 months even with treatment. Favorable prognostic factors include associated neurofibromatosis; long history of symptoms (>12 months); exophytic location; low-grade histology; focal tectal and cervicomedullary tumors; and calcification. Poor prognostic indicators include age < 2 years; multiple brainstem signs; cranial nerve palsies; diffuse pontine lesion; short history; and (6) high-grade histology on biopsy.
Medulloblastoma
Medulloblastoma is the most common brain tumor in children accounting for approximately 7-8% of all intracranial tumors and 30% of pediatric brain tumors. It was originally described by Bailey and Cushing in 1925, and is now thought to arise from neural stem cell precursors in the granular cell layer of the cerebellum. It has a high propensity of spreading throughout the neuraxis via the cerebrospinal fluid (CSF). Extraneuraxial systemic metastases though well recognized are uncommon. Although predominantly a pediatric tumor, medulloblastoma can affect patients of any age from neonates to the elderly. Three quarters of all cases occur in children, with a median age of 9 years at presentation. Vast majority occur as sporadic cases, but hereditary conditions associated with medulloblastoma are also described. These include (1) Gorlin syndrome (nevoid basal cell carcinoma syndrome), (2) blue rubber-bleb nevus syndrome,
(3) Turcot syndrome (eg, glioma polyposis syndrome), and (4) Rubinstein-Taybi syndrome.
The common presenting features include 1) Hydrocephalus: The younger, nonverbal patient presents with behavioral change. Symptoms in younger children include listlessness, irritability, vomiting, and decreased social interactions. Older children and adults complain of headache, especially upon awakening in the morning. Projectile vomiting without nausea is common in the morning. Visual disturbances may present a s diplopia or reduced vision due to papilledema. 2) Cerebellar symptoms: Commonly causes truncal ataxia and dysmetria. Head tilt and neck stiffness, caused by meningeal irritation, are complications of tonsillar herniation below the foramen magnum. 3) Leptomeningeal dissemination: Presenting symptoms rarely are related to dissemination of tumor in the CSF. Patients can complain of severe weakness from tumor compression of the spinal cord or nerve roots (eg, radiculopathy).
The diagnosis of medulloblastoma is established on the basis of histological criteria. Medulloblastoma is currently divided into WHO-defined subsets including classic medulloblastoma and the large-cell anaplastic, desmoplastic, medullomyoblastoma, and melanotic variants—on the basis of light microscopy and immunohistochemical findings. However, for clinical purposes patients are most commonly separated into classic, desmoplastic, anaplastic or large-cell, and nodular variants. Sheet-like areas of small, round, blue cells with scant cytoplasm and dense hyperchromatic nuclei are the hallmark features of classic, undifferentiated medulloblastoma. Homer–Wright rosette patterns, consisting of a circular nuclear array with tangled cytoplasm, are seen in less than half of medulloblastomas. Mitosis is seen in up to 80% of tumours, as assessed by positive staining with the Ki-67/MIB1 antibody. Medulloblastomas are frequently positive for vimentin and synaptophysin staining. The desmoplastic medulloblastoma variant is composed of highly proliferative, densely packed, reticulin-rich, mitotically active areas that surround riticulin-free nodules. Within the nodules there is a paucity of mitosis and cells that are immunoreactive for synaptophysin, neuron-specific enolase, and various neurofilaments. Perinuclear halos, which look like oligodendrogliomas, are occasionally seen. Desmoplastic variants are seen in up to 50% of adult cases of medulloblastoma compared with 15% in children.
Molecular biology of medulloblastoma
The understanding the pathogenesis of the medulloblastoma continues to evolve. Though not conclusively established, it has been postulated to arise from the two germinomal zones of the cerebellum: the ventricular zone, which contains multipotentional stem progenitors, for classic and midline tumours, and the external granular layer for the less common, laterally placed and often desmoplastic tumours that possibly arise from more restricted neuronal progenitor cells. Signal transduction mechanisms that promote oncogenesis, which include a range of regulatory checkpoints at the level of cell signalling receptors, intracellular second messengers, transcription factors, and gene regulation have also been an active area of research and include:
Sonic hedgehog pathway: Sonic hedgehog (Shh) is a member of a family of evolutionarily conserved proteins whose function is to mediate growth-promoting signal transduction for normal cerebellar development. Shh signalling is negatively regulated by its receptor, Patched 1. The role of Shh in medulloblastoma was first discovered through the observation that inactivating mutations of the gene encoding Patched 1 (PTCH1) on chromosome 22 result in familial nevoid basal cell carcinoma (Gorlin’s syndrome), and patients with Gorlin’s syndrome are prone to medulloblastoma. Approximately 10–30% of patients with sporadic medulloblastoma also have mutations in PTCH1 or other Shh-pathway-activating mutations. Additional evidence for the involvement of the Shh pathway is seen in patients with a deletion of chromosome 17p, which is the most common genetic aberration in medulloblastoma and is associated with poor prognosis.
Wingless pathway: Wingless (Wnt) is a family of growth factor receptors that are involved in embryogenesis and act through gene regulation and cell–cell control mechanisms. Wnt is involved in the transcriptional regulation of several genes that control the cell cycle, including MYC, NMYC, and cyclin D. Up to 20% of medulloblastomas contain mutations in the Wnt pathways, and an increase in MYC mRNA is associated with lower survival. Overexpression of MYC causes anaplasia in medulloblastoma. â-Catenin, a nuclear transcription factor in the Wnt pathway, might also have a role in medulloblastoma signalling.
Receptor tyrosine kinases: Four members of the family of receptor tyrosine kinases (epidermal growth factor receptor [EGFR], platelet-derived growth factor receptor [PDGFR], nerve growth factor receptor [NGFR], and neurotrophin-3 receptor [TrkC]) are associated with medulloblastoma and have been a focus of research into small-molecule biological therapy. EGFR is part of a large family with four members, ErbB1–ErbB4, of which ErbB2 (HER2/Neu) is most highly expressed, comprising up to 84% of all proteins expressed in medulloblastoma. Neurotrophin-3 receptor (TRKC) was the first receptor tyrosine kinase to be associated with clinical significance in embryonal tumours: increased expression of TRKC is a favourable prognostic indicator in medulloblastoma, possibly through apoptotic regulation of proliferating cerebellar granular cells.
The retinoid pathway, Notch/CXCR4 signalling axis and inhibitors of apoptosis proteins have also been variably associated with tumorigenesis in medulloblastoma
Risk stratification
Staging and subsequent risk stratification are crucial in the management of medulloblastoma. Current staging classification requires analysis of the CSF and MRI of the brain and entire spine with gadolinium. CSF from the lumbar region is preferred because it is more sensitive than ventricular fluid for detecting disseminated disease. CSF should be obtained from the lumbar region 2 weeks postoperatively to avoid the false-positive cytology from the initial resection. Assessment of the CSF for disseminated disease is crucial because up to 10% of adults and 30% of children have evidence of disseminated disease at presentation. M0 staging is assigned if there is no evidence of disseminated disease, whereas M1 staging denotes malignant cells in the CSF. Patients with tumours that are seen on MRI have M2–M3 classification. M4 staging is assigned if there is extraneural spread, which is usually seen in infants and less than 1% of all patients with medulloblastoma. Patients are generally divided into risk-adapted schemes on the basis of age, the extent of residual disease, and metastases. Patients older than 3 years are assigned to the average-risk category if they have a gross or near-total resection, which is arbitrarily defined as d”1.5 cm2 of postoperative residual disease. High-risk disease include patients <3 years of age, or metastatic disease at presentation or >1.5 cm2 residual tumor.
The cornerstone of treatment is surgery in the form of maximal safe resection followed by adjuvant radiotherapy (craniospinal irradiation followed by tumor bed boost). Adjuvant chemotherapy is indicated in high-risk disease with standard dose CSI or in average risk disease whenever CSI is reduced. Apart from providing histologic confirmation, surgery also has the added benefit of restoring the natural CSF pathways in the brain. A majority of patients will have resolution of their hydrocephalus after surgery. At the time of surgery, the extent of subarachnoid spread of the tumor can be assessed. In one third of cases, the tumor adheres to the floor of the fourth ventricle, precluding gross total resection. Postoperative imaging preferably an MRI should be done within 48 hours of surgery to assess the extent of resection and help in assigning risk. CSF diversion in the form of a ventriculoperitoneal shunt for long-term control of hydrocephalus is needed in only approximately 15% of patients. The alternative to shunting is a third ventriculostomy.
With current multimodality therapy, nearly 80% of children with average-risk, non-disseminated medulloblastoma have a 5-year event-free survival, which reduces to 50–60% for high-risk disease. The outcome for younger children, particularly infants, is worse. Children who survive medulloblastoma are at risk of long-term sequelae related to the neurological effects of the tumor, surgery, radiotherapy, and chemotherapy.
Adjuvant chemotherapy has become an integral part of treatment for medulloblastoma (MB). Several chemotherapeutic agents (especially alkylators and platinums) have been shown to be effective against medulloblastoma, and various chemotherapeutic strategies have been studied. In North America, the most widely used agents include lomustine, cisplatin, vincristine, cyclophosphamide and “standard” adjuvant chemotherapy consists of vincristine during radiotherapy and lomustine, cisplatin, and vincristine administered post-radiotherapy. Chemotherapy is usually administered for approximately 1 year after completion of radiotherapy. In Europe, various multiagent chemotherapeutic schedules have been investigated, many of which have included high-dose methotrexate. The distinct approaches used by the different studies make direct comparisons between studies problematic and preclude definitive conclusions regarding the most efficacious chemotherapeutic agents. For average-risk patients, chemotherapy has permitted successful reduction in CSI dose while maintaining survival rates. In patients with high-risk disease, with historical 5-year PFS rates of only 25% to 40% when treated with radiotherapy alone, the addition of adjuvant chemotherapy has increased the 5-year PFS to approximately 60%. The timing of chemotherapy in relation to radiotherapy is critical. Several European studies have demonstrated that the use of prolonged preradiotherapy chemotherapy negatively affects outcome for average- and high-risk patients, presumably because of delays in the delivery of radiotherapy. Currently, chemotherapy is used to augment radiation therapy to effect greater survival rates in high-risk MB or to allow a reduction or delay in CSI for pediatric patients with average-risk disease. Chemotherapy has not been proven to offer superior outcomes for adult MB patients, and adult patients poorly tolerate commonly used pediatric regimens. Therefore, the role of chemotherapy in the treatment of adult MB in first remission remains unclear.
High-Risk Disease
The contemporary “standard” therapy for children with medulloblastoma consists of maximal surgical resection followed by standard dose craniospinal irradiation (36 to 39.6 Gy with boosts to metastatic sites boost to the PF (total dose 55.8 Gy)combined with adjuvant chemotherapy.The first trials to demonstrate the benefits of adjuvant chemotherapy in newly diagnosed high-risk MB were conducted by the Children’s Cancer Group (CCG) and the International Society of Pediatric Oncology (SIOP). These trials employed 3,600 cGy CSI and a boost to the posterior fossa to 5,400 to 5,600 cGy, as well as a randomization between no additional therapy or adjuvant chemotherapy. The CCG study used a regimen of vincristine concurrent with radiation followed by post radiation vincristine, prednisone, and CCNU. The SIOP study used a similar construct without prednisone. Both trials demonstrated a significant benefit from the addition of chemotherapy, particularly for those patients with the largest tumor burden. Other regimens demonstrating efficacy include vincristine and cyclophosphamide, vincristine, CCNU, and cisplatin, and vincristine, cyclophosphamide, and cisplatin. Current clinical trials employing radiation therapy include the use of radio sensitizing chemotherapy or post radiotherapy high-dose chemotherapy utilizing peripheral blood stem cell (PBSC) rescue in patients greater than 3 years of age. Children’s Oncology Group (COG) 99701 and Tata Memorial Hospital protocols use carboplatin and vincristine concurrent with irradiation followed by alternating cycles of cyclophosphamide with vincristine and cyclophosphamide, vincristine, and cisplatin. The COG 99702 protocol contains vincristine concurrent with radiation followed by three cycles of high-dose chemotherapy (two of carboplatin and thiotepa and one of carboplatin, cyclophosphamide, and vincristine) supported by PBSC rescue. A multi-institutional study coordinated by St. Jude Children’s Research Hospital (named SJMB96) adopted an alternative therapeutic strategy, using sequential courses of nonmyeloablative high-dose cyclophosphamide with stem cell support to assist hematopoietic recovery, in order to facilitate dose intensity. Cumulative doses of cisplatin and vincristine were reduced to decrease the significant late effects produced by these agents. High-risk patients received 36 to 39.6 Gy CSI with boosts to metastatic sites and a three-dimensional conformal boost to the PF (total dose 55.8 Gy).The 4-year PFS rate increased to 72% ± 8%, and moreover, patients with metastatic disease (M+) fared particularly well with this approach, achieving a 4-year PFS rate of 68% ± 9% These results suggest that intensified chemotherapy with stem cell support is a feasible and promising therapeutic option for patients with medulloblastoma, especially for patients with metastatic disease.
Average-Risk Disease:
In the only large randomized trial to compare chemotherapy plus radiation versus radiation alone, the SIOP/UKCCSG PNET-3 study showed superior EFS for those patients receiving pre-irradiation chemotherapy consisting of vincristine, etoposide, carboplatin, and cyclophosphamide followed by 3,500 cGy CSI and a 2,000-cGy posterior fossa boost. EFS at 5 years was 74.2% versus 59.8% (P < .0366), but OS was not significantly different. Chemotherapy has also been explored as a means to improve survival while allowing a reduction in the CSI radiation dose to lessen the neuropsychological and endocrinologic effects of radiation to the developing neuraxis. The CCG tested this concept in a trial with 65 patients by reducing the craniospinal dose from the standard 3,600 cGy to 2,340 cGy, while maintaining the posterior fossa boost to 5,580 cGy total dose and adding adjuvant chemotherapy consisting of vincristine, cisplatin, and CCNU. Progression-free survival was 86% at 3 years and 79% at 5 years. These rates compare favorably with historical controls. A recent CCG phase III clinical trial of 421 patients with nondisseminated average-risk medulloblastoma randomized children to one of two regimens of post radiation chemotherapy and assessed 5-year event-free survival (EFS). Not only did this demonstrate a high rate of 81% 5-year EFS with 23.4-Gy CSI, but, as the largest trial to date in medulloblastoma, it established comparable EFS in the groups administered lomustine, cisplatin and vincristine or cyclophosphamide, cisplatin and vincristine. Less toxicity was seen from lomustine compared with cyclophosphamide.
SJMB96 trial using sequential courses of nonmyeloablative high-dose cyclophosphamide with stem cell support and reduced dose CSI (23.4 Gy) followed by a three-dimensional conformal boost to the PF (cumulative dose 36 Gy) and tumor bed (total dose 55.8 Gy). demonstrated 4-year PFS of 83% ± 5%, confirming that dose reductions are feasible not only for CSI but also for vincristine and cisplatin, without adversely affecting survival. Further reduction of the CSI dose to 1,800 cGy has been piloted in 10 patients less than 5 years of age, seven of whom enjoy long-term disease-free survival. The current COG average-risk trial includes a randomization between 1,800 and 2,400 cGy CSI, as well as a second randomization between a boost to the entire posterior fossa versus a boost to the focal tumor bed. All patients will receive post radiation chemotherapy with cycles alternating between cisplatin-based and cyclophosphamide-based regimens. Based on the results of these studies, contemporary “standard” therapy for children with average-risk medulloblastoma consists of maximal tumor resection followed by reduced neuraxis-dose irradiation (CSI 23.4 Gy, posterior fossa [PF] 55.8 Gy), combined with adjuvant chemotherapy. This however, mandates strict quality assurance during planning and delivery of radiotherapy. Alternative hyperfractionated protocol (see appendix) without chemotherapy could be considered as a reasonable alternative, as per the institutional policy.
Infant Medulloblastoma
In children less than 3 years old for whom the long-term neurocognitive sequelae of radiotherapy are unacceptable, chemotherapy has been used in an attempt to delay or eliminate the need for radiation. Given the relative scarcity of these young brain tumor patients, data relevant to MB must be gleaned from studies that include all malignant brain tumors, of which MB makes up the majority. Many different chemotherapeutic combinations of varying intensity have been used. In one Pediatric Oncology group (POG) study, children under 36 months of age with malignant brain tumors were treated postoperatively with combinations of cyclophosphamide/vincristine and cisplatin/ etoposide for 1 or 2 years depending on the age at diagnosis (roughly until age 3). After this, the patients received radiation therapy. Complete or partial responses were noted in 39% of patients. The progression-free survival rate at the completion of chemotherapy was 40%. The CCG used an eight-drug post-operative chemotherapeutic regimen including vincristine, carmustine, procarbazine, hydroxyurea, cisplatin, cytarabine, prednisone, and cyclophosphamide for patients less than 3 years of age, 56% of whom had MB. Objective tumor response was noted in 28% of all patients following two cycles of chemotherapy. The 3-year progression-free survival rate for MB was 22% ± 6%. Metastatic disease was found to be a poor prognostic factor.
A recent multi-institutional study from Germany has reported very encouraging results in 43 children aged younger than 3 years treated with chemotherapy intensified with intravenous and intrathecal methotrexate without radiotherapy; the 5-year PFS for the whole group was 58%. Moreover, patients without evidence of macroscopic metastatic disease or postoperative residual tumor (n = 17) had an excellent 5-year PFS of 82% ± 9%. Only patients with macroscopic metastatic disease faired poorly (5-year PFS 33% ± 14%). However, a caveat to these results is the alarming incidence of asymptomatic leukoencephalopathy noted on MRI, most likely attributable to the intensive use of methotrexate. Moreover, although the mean IQ of survivors was higher than historical controls that received whole brain radiotherapy, it was significantly lower than age-matched controls. Current treatment approaches for infants therefore include chemotherapy for induction and consolidation. At the completion of chemotherapy, the use of focal radiotherapy should be considered individually based on age, clinical status, extent of original disease, and tumor response.
Supratentorial PNET
Although numerous reports show distinct genomic and biologic features in relation to the precise location of a primitive neurectodermal tumour (PNET), whether in or outside of the posterior fossa, most of the trials published to date, however, have tended to use the same protocol for both types of tumour, only considering children with supratentorial PNET as a separate high-risk category. Where separate analyses are available, supratentorial PNET is always shown to have a lower response rate and an inferior overall prognosis. Various single-agent and combination chemotherapeutic regimens used for medulloblastoma have shown activity against sPNET. In the CCG 921 study in which neoadjuvant and adjuvant 8-in-1 chemotherapy was compared to adjuvant CCNU, prednisone, and vincristine, each given with radiation therapy, 3-year PFS and survival were 45% and 57%, respectively, for all patients with sPNET and did not differ significantly between the two study arms. Whether use of chemotherapy increased survival from that historically reported with surgery and radiation therapy alone was unclear from this study. Ongoing clinical trials offer combined-modality therapy as used for high risk medulloblastoma to infants and older children with sPNET.
Atypical Teratoid-Rhabdoid Tumors (ATRTs)
Given the young age of the patients, chemotherapy has been the primary modality after surgery and RT. AT/RTs appear to be chemosensitive tumors with retrospective series reporting complete or partial responses in more than 50% of children with incomplete resections. A wide variety of chemotherapy regimen used for infantile brain tumors and sarcoma like regimens have been used, most commonly using alkylators, vincristine, and platinum based combinations. Unfortunately for most patients, multiagent chemotherapy including myeloablative chemotherapy with or without radiation therapy is not curative. The optimal chemotherapy and treatment regimen for AT/RTs remains unknown. Several limited institution clinical trials are addressing the role of high-dose chemotherapy with stem cell rescue for children with AT/RT along with early focal RT.
Primary CNS germ cell tumors:
Therapy for malignant intracranial GCT is stratified according to the histologic differentiation (i.e. germinoma vs. secreting GCT) and initial dissemination. For patients with germinoma, chemotherapy has been added to radiotherapy to decrease deleterious late effects of radiation therapy. For the nongerminomatous tumors, chemotherapy has been added to try to improve cure rates.
Germinomas:
Germinomas are highly chemotherapy-sensitive tumors. Regimens that use cisplatin, carboplatin, or cyclophosphamide, along with vinblastine or vincristine, bleomycin, and etoposide, are capable of producing complete and partial response rates in as high as 90% in newly diagnosed patients. The current focus centers on the optimal balance of chemotherapy and radiation therapy. Many recent studies have examined the use of chemotherapy with either reduced-dose radiation therapy or without radiation altogether. In the largest series wherein chemotherapy was used alone, despite high rates of response, 50% patients ultimately relapsed, and the 2-year overall survival rate was only 84%. Hence, treatment with chemotherapy alone in germinoma is not recommended outside of a clinical trial setting. Studies of chemotherapeutic regimens followed by radiation therapy at doses reduced to 30.6 and 40.0 Gy have shown high response rates and survival rates nearing 100%. Hence, the use of chemotherapy and radiation therapy for intracranial germinomas is rational and effective, although the optimal schedule must be determined. In current SIOP CNS GCT 96 and TMH protocol, patients with germinoma and localized disease are treated with a multimodal treatment including two cycles of chemotherapy (PEI) followed by a whole ventricular irradiation (40 Gy). In metastatic disease, craniospinal irradiation and boost to tumor and the metastatic sites is the treatment of choice along with chemotherapy. Patients undergoing chemotherapy for germ cell tumors need to be monitored carefully with respect to their endocrine and biochemical parameters, as a proportion of them may experience such abnormalities. In some instances in older children, patients are treated with CSI alone, without chemotherapy, to a dose of 25 Gy/14 fractions followed by local tumour bed boost of 15 Gy/9 fractions.
Nongerminomatous germ cell tumors (NGGCT):
The secreting intracranial NGGCT show an inferior prognosis compared to germinoma. In NGGCT, with standard chemotherapeutic regimens along with radiation, response rates exceeding 80% and survival rates of 48% to 80% have been seen. Relapse rates appear to be higher in the patients treated with involved field RT only. Therefore, craniospinal irradiation for all patients is advisable. At TMH, these patients receive 4 cycles of cisplatinum based chemotherapy (PEI, appendix) are applied, followed by a delayed tumor resection and craniospinal irradiation (30-35 Gy plus 20-24 Gy tumor boost).
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PRIMARY CENTRAL NERVOUS LYMPHOMA
Primary Central Nervous System Lymphoma (PCNSL) is a rare form of extranodal high-grade non-Hodgkin B-cell neoplasm, usually large cell or immunoblastic type, originating in the brain, leptomeninges, spinal cord, or eyes, and typically remains confined to the CNS. Previously, a rare tumor accounting for less than 1% of cerebral neoplasms, PCNSL is now being seen with increasing frequency in immunocompetent patients, patients with AIDS, and transplant recipients, and accounts for 2.7% of all primary brain tumors in the United States. Most PCNSLs (about 90%) are diffuse large B-cell lymphoma (DLBCL); the remaining 10% are poorly characterized low-grade lymphomas, Burkitt lymphomas, and T-cell lymphomas. PCNSL arises from B lymphocytes, which are usually small, noncleaved, or immunoblastic cells. The DLBCL type of PCNSL is composed of immunoblasts or centroblasts that have a predilection for blood vessels. Lymphoid clustering around small cerebral vessels is typically seen. Reactive T-cell infiltrates can also be present in varying degrees. Its predilection for certain cerebral sites gives rise to the characteristic appearance on neuroimaging studies. Seventy-five percent of immunocompetent patients with these tumors have solitary lesions. The dense cellularity of the tumor accounts for its isodense or hyperdense appearance on nonenhanced CT scan and hypointense appearance on long TR-weighted MRI. Following administration of either iodinated contrast for CT or gadolinium for MRI, almost all PCNSLs enhance homogeneously. PCNSLs are assumed to be diffusely infiltrative at the time of presentation. The areas of disease are not visible on neuroimaging studies because they are behind a relatively intact blood-brain barrier. Primary symptoms may result from local mass effect due to raised intracranial pressure, from ocular involvement, or from focal deposits on cranial or spinal nerve roots. Median age of immunocompetent patients with PCNSL is 55 years. Median age of HIV-infected patients with PCNSL is 35 years.
The most typical presentation of PCNSL in an immunocompetent patient is progressive focal symptoms indicative of a mass lesion. Seizures may occur. Sometimes, nonspecific mental status change leads to the diagnosis. Patients with AIDS are more likely to present with an encephalopathy than other patients with PCNSL. This correlates with the more often multifocal, diffuse enhancement pattern seen on MRI. A history of concurrent infections is quite common, and the median CD4+ count is 20/mm3. Much of the history taking should be devoted to establishing whether the patient may have immune deficiency. A careful sexual and drug abuse history is necessary. If the patient is a transplant recipient, the nature and duration of immune suppression must be clarified. Diagnosis of PCNSL in both immunocompetent and immunocompromised patients is particularly difficult if they present with one of the variant syndromes as below:
1) Isolated, ocular, or meningeal tumor may occur in the absence of any focal abnormalities on MRI.
2) Relapsing, remitting lesions may disappear for periods as long as several months to a year or more.
3) Progressive dementia or stupor with no focal signs and with little or no enhancement on MRI may be more common in
patients with AIDS who have PCNSL.
4) Intravascular malignant lymphomatosis a series of stroke like focal events, with the imaging mimicking multiple large-
and small-vessel strokes.
Treatment
Stereotactic brain biopsy or open biopsy for selected patients is the most appropriate method for diagnosis of PCNSL with no justification for aggressive surgical debulking. The goal of treatment is eradication of both contrast-enhancing mass lesions and microscopic infiltration of brain, spine, leptomeninges, and vitreous. Successful therapy in immunocompetent patients leads to a median survival duration as long as 44 months. Treatment must be designed to maximize efficacy and minimize toxicity to cerebral white matter. The optimal treatment for PCNSL has not been established. Combination chemotherapy and radiation therapy have improved outcomes and are considered contemporary standard of care. The decision to offer chemotherapy as the sole initial treatment modality, therefore, must be made keeping in mind that optimal dose and timing are still under investigation. Methotrexate-based chemotherapy regimens have been the most successful treatment strategies to date, but need close monitoring and adjustment of intravenous fluids and calcium leucovorin rescue. Corticisteroids should avoided during the initial workup, as their administration may have a direct antitumor effect on B-cell lymphoma and cause dramatic reduction in the MRI abnormalities, making biopsy and histologic confirmation more difficult. Similarly, corticosteroids should be avoided, if possible, during chemotherapy, as repair of the blood-brain barrier may decrease the delivery of methotrexate into the brain parenchyma. Prophylactic use of antiepileptic drugs should be avoided and their use should be confined to patients who experience seizures.
With whole-brain radiation therapy which historically had been the primary treatment for PCNSL, the initial clinical and radiographic response was high, but the duration of response was short-lived and the median survival only 10-16 months for immuno-competent patients and 4 months for immuno-compromised patients. Chemotherapy (high-dose methotrexate based regimens) has dramatically improved outcome with a 5- year survival of 35-40% and median survival of 40-44 months. A subgroup of patients with AIDS who are able to tolerate chemotherapy and radiation therapy can have median survival duration >18 months. Given it occurs in older patients amongst the immunocompetent population, the neurocognitive toxicity of treatment (both whole brain radiation therapy and high-dose methotrexate) needs to be considered in the decision making.
MENINGIOMAS
Meningiomas are a group of tumors thought to arise from arachnoidal cap cells, which reside in the arachnoid layer covering the surface of the brain. They account for approximately 20% of all primary intracranial neoplasms. Meningiomas can be multiple in 10-40% of cases, particularly when they associated with neurofibromatosis-2 (NF-2). They afflict women more often than men, with a median age of 40 years at presentation. Usually slow growing tumors, meningiomas can produce severe morbidity before causing death. Factors that may be predictive of a high postoperative morbidity include patient-related factors (advanced age, comorbid conditions, preoperative neurological status), tumor factors (location, size, consistency, vascularity, grade), and treatment factors (resection, adjuvant therapy). They may cause symptoms by irritating the underlying cortex (seizures), compressing the brain or the cranial nerves (headache, palsies), producing hyperostosis and/or invading the overlying soft tissues, or inducing vascular injuries to the brain (focal deficits).
The best-characterized and most common (60%) genetic alteration in meningiomas is the loss of the NF-2 gene (NF2) on chromosome 22q, which encodes a tumor suppressor known as merlin (or schwannomin). Other cytogenetic alterations are chromosomal loss of 1p, 3p, 6q, and 14q. Loss of chromosome 10 is associated with increased tumor grade, shortened time to recurrence, and shortened survival. There is an association between hormones and the risk of meningiomas, including increased incidence in women and presence of estrogen, progesterone, and androgen receptors on some of these tumors. Cell phones have also been incriminated as causative agents.
The cornerstone of management is complete neurosurgical resection. From the neurosurgical perspective meningiomas can be classified as convexity, parasagittal, olfactory groove, tuberculum sellae, sphenoidal, tentorial, cerebellopontine angle, cavernous sinus, and petroclival meningioma. The guiding principles in meningioma resection are the following: If possible, all involved or hyperostotic bone should be removed. The dura involved by the tumor as well as a dural rim that is free from tumor should be resected (duraplasty should be performed). Dural tails that are apparent on MRI are best removed, even though some may not be involved with the tumor. Provision for harvesting a suitable dural substitute (pericranium or fascia lata) should be made and if feasible, start by coagulating the arterial feeders to the meningioma. Preoperative embolization should be considered in hypervascular meningiomas. For completely excised benign and low grade meningiomas, there is no role of any adjuvant radiation therapy. For atypical meningiomas or those invading the brain extensively, adjuvant radiation therapy may be used to improve local control and progression free survival. Postoperative adjuvant radiation therapy is indicated for subtotally excised or progressive low grade meningiomas and all high-grade (anaplastic) meningiomas. The estimated 5-year survival for low grade meningiomas varies from 70-90%. Malignant and atypical meningiomas have a far more aggressive clinical course with a 5-year survival of 40-60%. Chemotherapy has no role in the upfront management of meningiomas and remains purely investigational.
ACOUSTIC NEUROMA
Acoustic neuromas are intracranial extra-axial tumors that arise from the Schwann cell sheath investing either the vestibular or cochlear nerve. As acoustic neuromas increase in size, they eventually occupy a large portion of the cerebellopontine angle. Acoustic neuromas account for approximately 75% of tumors found within the cerebellopontine angle. Familial neurofibromatosis type II occurs in individuals who have a defective tumor suppressor gene located on chromosome 22. Bilateral acoustic tumors are a principle clinical feature of neurofibromatosis type II, although other manifestations, including peripheral neurofibromata, meningioma, glioma, and juvenile posterior subcapsular ventricular opacities, are often present as well. Peripheral neurofibromatoma and café au lait spots, however, are much less frequently observed than is typical in neurofibromatosis type I. Many patients with neurofibromatosis type II present in late adolescence or early adulthood. The vast majority of acoustic neuromas develop from the Schwann cell investment of the vestibular portion of the vestibulocochlear nerve. Overall, 3 separate growth patterns can be distinguished within acoustic tumors, as follows: (1) no growth or very slow growth, (2) slow growth (ie, 0.2 cm/y on imaging studies), and (3) fast growth (ie, >1.0 cm/y on imaging studies). Unilateral hearing loss is overwhelmingly the most common symptom present at the time of diagnosis and is generally the symptom that leads to diagnosis. Consistent with direct injury to cranial nerve VIII, a significant number of individuals with acoustic neuroma have speech discrimination scores reduced out of proportion to the reduction in the pure-tone average. Tinnitus can be the only presenting feature in up to 10% patients. Vertigo and dysequilibrium are uncommon presenting symptoms among patients with acoustic tumors. Facial numbness occurs in about 25% of patients and is more common at the time of presentation than facial weakness (about 10% of patients).
The algorithm for management of acoustic neuromas can be divided as (1) surgical excision of the tumor, (2) focal radiation therapy, or (3) careful serial observation. Microsurgical removal remains the treatment of choice for tumor eradication. Three different approaches are used in the management of acoustic neuromas, the retrosigmoid, translabyrinthine, and middle fossa approaches. Preoperative hearing levels, auditory brainstem responses, electronystagmography, size, location, and relevant neuroanatomy, surgeon or patient preferences are actors influencing the surgical approach. The operative mortality rates have dropped dramatically from 40% at the beginning of the century to less than 1% in the last decade. Postoperative facial paralysis, once the rule, is now an uncommon permanent sequela of acoustic tumor surgery. Stereotactic radiosurgery is a reasonable alternative to microsurgery in selected patients. In recent times, conventionally fractionated focal stereotactic conformal radiation therapy has shown very high local tumor control with excellent hearing preservation. Elderly patients, with very small tumors with preserved hearing with indolent growth kinetics can be put on surveillance, with intervention being reserved for progression. The long-term outcome of acoustic neuroma is excellent with reported 5-year and 10-year survivals upwards of 90% and 80% respectively, with decent hearing preservation in 30-60% of properly selected patients.
CRANIOPHARYNGIOMA
Craniopharyngioma is a histologically benign, extra-axial, slow-growing tumor that predominately involves the sella and suprasellar space. They are dysodontogenic epithelial tumors derived from the Rathke cleft, which is the embryonal precursor to the adenohypophysis. Three distinct subtypes primarily based on histologic appearance have been described: adamantinomatous, papillary, and mixed. The commonest type is the adamantinomatous tumor which is partly solid, partly cystic with characteristic machine oil fluid. Histologically, the cyst has a multistratified squamous epithelium with nuclear palisade, and the solid component demonstrates clumps of wet keratin, dystrophic calcifications, trabeculae, nests, and squamous or columnar epithelium. Craniopharyngioma represents approximately 3-5% of intracranial tumors and 6-10% of pediatric brain tumors. A bimodal age distribution is seen, with the first peak occurring in childhood and early adolescence, predominately at age 5-10 years. The second peak (for papillary types) occurs at age 40-60 years. The most common presenting symptoms are headache, nausea, vomiting, and visual disturbances. The most common visual disturbances are bitemporal hemianopsia, homonomous hemianopsia, and amblyopia. Other common findings include oculomotor palsies, bizarre scotomas, blindness, asymmetric acuity deficiencies, and optic atrophy. Hydrocephalus may result from a tumor that obstructs the third ventricle. In children, failure to thrive is a common presentation. Other presenting include those of pituitary and adrenal hypofunction, diabetes insipidus, obesity, weakness, ataxia, coma, chemical meningitis (from rupture of cyst contents into subarachnoid space), and seizures.
Craniopharyngiomas have been surgically divided into 3 groups: sellar, prechiasmatic, and retrochiasmatic. Three specific growth categories have also been described based on the relationship of the tumor to the vascular structures and the optic chiasm: type A, type B, and type C. In type A, the anterior communicating artery and the A1 segment of the anterior cerebral artery are not disturbed. In type B, the anterior communicating artery and the A1 segment of the anterior cerebral artery are elevated, but no posterior displacement of the basilar artery is observed. The tumor protrudes anteriorly between the optic nerves and pushes the optic chiasm posteriorly. In type C, the anterior communicating artery and the A1 segment of the anterior cerebral artery are elevated, with posterior displacement of the basilar artery and stretching of the posterior communicating arteries. The tumor protrudes posteriorly, pushing the chiasm forward and causing it to abut the tuberculum sellae.
The primary treatment of choice is complete surgical excision. Local recurrence is common after surgical excision alone, with reported recurrence rates of 25-40% without adjuvant radiation. The size of the tumor at presentation also impacts upon local recurrence (70% for tumors >5 cm and 20% for tumors <5 cm). Cystic degeneration and enlargement is a common finding on follow up scans and needs intervention in almost 20% of patients. In recent times conservative surgery (maximal safe resection) followed by adjuvant radiation therapy is preferred to aggressive radical excision to improve outcome. A 5-year survival rate of 70-80% is achieved with contemporary microsurgery and adjuvant radiation therapy. The 10-year overall survival is
60-75%.
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