Glioma is a general name for any primary CNS tumor of glial origin. Gliomas may be classified by cell type, grade and location. Gliomas of different cell types include astrocytoma, ependymoma, oligodendroglioma, oligoastrocytomas, ganglogliomas and optic nerve glioma. Location may be supratentorial or infratentorial, meaning above or below the tentorium, a meningeal layer that separates the cerebrum from the cerebellum and brainstem. Supratentorial locations are more common in adults and infratentorial locations are more common in children. Grading is based on tumor pathology and involvement. WHO grades I-II are generally benign while III-IV are malignant. WHO grade I has low proliferation rate and may be cured with surgical resection alone1. These typically occur in younger individuals, for instance, juvenile pilocytic astrocytoma. WHO grade II is more infiltrative but still has pathologic features of benign tumors including well-differentiated cells. With recurrence, these tumors may progress to malignancy1. WHO grade III tumors have malignant features, including high mitotic activity and nuclear atypia1. These should be treated with adjuvant radiation and/or chemotherapy in addition to surgical resection. Astrocytomas broadly can be WHO grade I-III. WHO grade IV lesions are cytologically malignant, mitotically active, necrosis-prone neoplasms with poor prognoses1. These include glioblastoma multiforme and embryonal tumors.
Glioblastoma multiforme (GBM) is the most severe presentation of astrocytoma, classified as WHO Grade IV. Distinguishing criteria include microvascular proliferation and necrosis.
There are 3 known genetic pathways that may be dysregulated: receptor tyrosine kinase (RTK), phosphatidylinositol-3-OH kinase (PI3K)/AKT/mTOR, and the p53 and retinoblastoma (Rb) tumor suppressor pathways.
Primary GBMs comprise the majority of GBMs, most commonly occurring in older patients (mean age 55 years) with a rapid clinical course.
Figure : Glioblastoma multiforme (GBM) A: Axial T1-weighted MRI with contrast. B. Sagittal T1-weighted MRI. C. Coronal T1-weighted MRI.
Secondary GBMs arise from malignant degeneration of WHO grade II or III astrocytomas in younger patients (mean age 40 years) and progress more slowly than primary GBMs.
The endpoints of surgery for GBMs are cytoreduction, relieving mass effect, and obtaining tissue for histological and molecular analysis. Standard therapy for GBM combines surgery, radiation, and temozolomide (temodar) chemotherapy. Temodar is member of the oral alkylating agent class of chemotherapeutic agents. It is metabolized to an active agent at physiological pH, which has a cytotoxic effect on tumor cells due to addition of alkyl groups to DNA. This typically causes irreparable damage to tumor DNA in addition to side effects due to damage of host DNA, typically in fast growing cells (i.e. hair and gastrointestinal mucosa). Surgical resection should aim for gross total resection with preservation of eloquent and critical structures. Awake craniotomy is performed for lesions in eloquent brain regions. Studies have shown that excision of 97% or more of a GBM is associated with increased survival time and likely also improves time to tumor progression.
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5-aminolevulinic-acid (5-ALA) may be used to visually identify the tumor intraoperatively. It is metabolized into fluorescent porphyrins that are taken up by malignant glioma cells.
Partial GBM resection carries risk of postoperative hemorrhage and/or edema, known as wounded glioma syndrome, with risk of herniation. Therefore, patients with extensive, multicentric, or bilateral cortical involvement are not candidates for surgical debulking.
Patients who are not surgical candidates due to tumor location in eloquent or inaccessible areas of the brain or inability to undergo general anesthesia may undergo stereotactic biopsy instead. However, stereotactic biopsy may underestimate GBM in up to 25% of cases due to sampling error.
Recurrent GBM may be treated with the chemotherapeutic agent Bevacizumab, known as Avastin. It is a recombinant human monoclonal antibody that prevents the proliferation of blood vessels by blocking vascular endothelial growth factor A (VEGF-A). Cancers such as GBM upregulate VEGF concentrations to promote angiogenesis for supporting growth of the tumor cells. Avastin has increased tendency to bleed as a side effect and is reserved for recurrent glioblastomas. Other chemotherapeutic agents include Nivolumab (Opdivo). Nivolumab is a human monoclonal antibody directed against the negative immunoregulatory human cell surface receptor Programmed death-1 (PD-1). Nivolumab binds and blocks the activation of PD-1. Activated PD-1 inhibits T-cell activation and effector function through the suppression of P13k/Akt pathway activation.
Brainstem gliomas are a heterogenous group of low and high grade tumors that typically present with cranial nerve palsies and white matter tract findings. They are more likely to occur during childhood and adolescence, with 77% of those affected less than 20 years of age. They are also more likely to be malignant and invasive. Common symptoms include gait disturbance, headache, nausea and vomiting, diplopia, facial asymmetry, distal motor weakness, papilledema, and hydrocephalus depending on the tumor location in the brainstem. Patients less than 2 years of age may present with failure to thrive.
Lower grade tumors have a predilection for the upper brainstem, while high grade tumors (such as glioblastoma) are more likely to arise in the lower brainstem. The four growth patterns of brainstem gliomas are diffuse, cervicomedullary, focal, and dorsally exophytic. All diffuse tumors are malignant, most being anaplastic astrocytomas and glioblastomas. In contrast, most cervicomedullary and focal neoplasms are low-grade astrocytomas. Dorsally exophytic tumors may be an extension of the focal growth pattern, with many being low grade gliomas including pilocytic astrocytomas and gangliogliomas. Surgery is only recommended for removal of dorsally exophytic tumors with radical subtotal resection. Complications include exacerbation of pre-operative symptoms such as ataxia and cranial nerve palsies, although these usually resolve over time. Long-term survival tends to be favorable with low incidence of disease progression at follow-up. Radiation therapy is the next in line for treatment when surgery is not possible. Most children with malignant brainstem gliomas die within 6-12 months of diagnosis.
This is a subgroup of brainstem gliomas mainly comprised of low-grade astrocytomas. The average age of presentation is 6-14 years of age. The most common complication is obstructive hydrocephalus, with associated symptoms of headache, nausea, and vomiting. Focal neurologic deficits are rare, and may include gaze disturbances. Long-term management with Endoscopic Third Ventriculostomy (ETV) or Ventriculoperitoneal shunt (VPS) for hydrocephalus is recommended, due to low risk of progression and morbidity of surgery. Tumor progression is described in 15-25% of cases and may be treated with stereotactic radiosurgery. (See figure)
Figure : Axial T1-weighted MRI with contrast showing tectal glioma with obstructive hydrocephalus.
Pontine gliomas are another subtype of brainstem gliomas, also known as diffuse intrinsic pontine glioma. These are generally malignant, aggressive, infiltrative tumors with a poor 5-year survival rate of <1%. Children are mainly affected. Symptoms are due to cranial nerve palsies, including problems with eye and facial movements, speech, chewing, and swallowing. Other symptoms include extremity weakness and ataxia. Due to the infiltrative nature of these neoplasms in a sensitive brain region, surgical resection is not recommended. Radiation therapy is first-line for palliative therapy with symptomatic improvement. However, rapid progression still occurs within a year of treatment. Chemotherapy is experimental at this time.
Chordomas are rare tumors with an incidence of 0.51 cases/million arising from the remnant of the primitive notochord, which typically develops into the nucleus pulposus of the intervertebral disks. Although they may arise anywhere along the neuroaxis, they tend to arise at the two ends of the primitive notochord. 35% occur at the cranial end in the spheno-occipital region at the clivus and 53% occur in the spine at the sacrococcygeal region.
Cranial chordomas occur most frequently in patients 50-60 years of age with an approximately equal male:female incidence. The most common presentation is of cranial nerve palsy typically involving the oculomotor or abducens nerve. In contrast, spinal chordomas occur more commonly in males and in older patients. As they most commonly occur in the sacrum, presenting symptoms include pain, sphincter disturbance, or nerve root symptoms from local nerve root compression.
These tumors are generally slow growing, locally aggressive, and osseodestructive. They are difficult to excise completely, have a high recurrence rate, and can metastasize in late stages, most commonly to the lung, liver, and bone. Pathologically they are distinguished by physaliphorous cells, a type of vacuolated cells likely representing cytoplasmic mucus vacuoles. Radiographically chordomas appear lytic with calcifications, and they enhance on CT with contrast. Bony destruction is commonly seen on CT and MRI with spinal chordomas.
Gold-standard treatment is wide en-bloc surgical excision with postoperative radiation, including high-dose radiation such as proton beam therapy. There is a high risk of surgically induced metastasis, which is reduced by piecemeal tumor removal. Decompression should be avoided for this reason. Resection of sacral chordomas is complicated by injury to nerve roots responsible for bowel and bladder function risking incontinence. If the nerve roots extending up to S1 are spared, there is a 50% chance of retaining normal bowel and bladder control. If the S1 level is not spared, the patient will likely have impairment of bowel and bladder continence. (See figure)
Figure : Cranial chordoma. A. Axial T1-weighted MRI with contrast B. Coronal T1- weighted MRI with contrast. C. Sagittal T1-weighted MRI with contrast.
CNS lymphomas may be classified as primary or secondary. Primary CNS lymphoma is a rare, malignant neoplasm that originates with the CNS and comprises 0.85-2% of all brain tumors. Men are more commonly affected, with a male: female ratio of 1.5:1. The median age at diagnosis is 52 years. These may occasionally metastasize outside the CNS. Immunocompromised patients such as AIDS and transplant patients are more likely to be affected than the general population. They also have a younger overall median age of diagnosis at 34 years. Primary CNS lymphoma may occur supra- or infratentorially. Supratentorial locations include the frontal lobes and basal ganglia as well as periventricular regions. The most common infratentorial location is the cerebellum.
Secondary CNS lymphoma is due to metastatic spread of systemic lymphoma, usually non-Hodgkin’s lymphoma, generally occurring in 1-7% of all lymphoma patients.
Primary and secondary CNS lymphoma present in similar ways. The most common symptoms arise from epidural spinal cord compression and carcinomatous meningitis, with multiple cranial nerve deficits. Seizures also commonly occur. Other non-focal, non-specific symptoms include mental status changes and symptoms indicating increased intracranial pressure, including headache and nausea and vomiting. Focal symptoms such as hemimotor or hemisensory deficits, aphasia, and visual field deficits may also be present.
First-line treatment following biopsy is radiation therapy with choice of adjuvant chemotherapy. For large tumors causing mass effect, severe perifocal brain edema and/or seizure, total resection is preferred. Chemotherapy has been shown to prolong survival in non-immunocompromised patients. Choice agents are methotrexate and rituximab. Generally, surgery is only for biopsy and confirmation of diagnosis but for larger lesions causing mass effect or severe edema or intractable seizure, total resection during open biopsy is recommended. These tumors are also highly responsive to steroids. Unfortunately, recurrence rate is high at 78% at 15 months following treatment. Median survival after radiation is 10 months, with 5-year survival 3-4%. One-year survival after gross total resection is estimated to be 56.6% and 31.8% following partial resection1. Intraventricular methotrexate has been shown to prolong median time to recurrence to 41 months. Prognosis is worse in immunocompromised individuals such as AIDS patients, with median survival only 3-5 months. This is generally due to opportunistic infection and not CNS complications.
A chondrosarcoma is a malignant cartilaginous tumor. They are lobulated tumors with calcifications. Despite the name, it is clinically a less aggressive tumor than chordomas. However, it is resistant to chemotherapy and radiation. Symptoms include back or thigh pain, sciatica, bladder problems, and unilateral edema. Surgical resection is the mainstay of therapy.
Esthesioneuroblastoma, also known as olfactory neuroblastoma, is a malignant tumor arising from the neural crest cells of the upper nasal tract that commonly extends intracranially. It is extremely rare, with an annual incidence of 0.4 per 1,000,000 people. It affects a wide age group ranging from 3 to 90 years, with one peak between the second and third decade of life and a second peak between the sixth and seventh decades. The most common symptoms are epistaxis (76%), nasal obstruction (71%), tearing (14%), pain (11%), diplopia, proptosis, anosmia, and endocrinopathy. MRI can be used for imaging. Treatment is most commonly with surgical resection followed by radiation therapy. Chemotherapy may be added on as well, of which platinum-based chemotherapy is the standard. Diagnostic biopsy is typically done by otolaryngology in office prior to surgery. The Kadish system is most commonly used to clinically classify extent of disease and correlates with survival:
- A: Confined to nasal cavity
- B: Extension to paranasal sinus
- C: Local extension (orbit or cribiform plate)
- D: Distant metastasis
Pathologic grading may be undergone using the Hyams grading system, which is used to classify all upper respiratory tract carcinomas for nuclear pleomorphism, mitotic activity, presence of rosettes, necrosis, and summates. Grade 1 and 2 lesions have been shown to have a benign disease course while grades 3-4 confer a poor prognosis.
Surgical treatment involves endoscopic tumor resection. Should the tumor extend to the inferior lateral orbit or maxilla, lateral rhinotomy may be utilized to access and excise the lesion. Many institutions use a purely endoscopic approach so long as negative margins are obtained. If not, conversion to an open approach is necessary. Some institutions may opt for stereotactic radiosurgery instead.
The mean overall survival is 7.2 ± 0.7 years. Mean progression free survival is 4.8 ± 0.7 years. Five-year survival is 63%, and 10-year survival is 40%. The most significant prognostic factors are Kadish staging, lymph node involvement, and age at diagnosis.
Choroid Plexus Carcinoma
Choroid plexus carcinoma is a malignant variant of the benign choroid plexus papilloma, a rare neuroepithelial tumor arising from the choroid plexus in the interventricular space. The choroid plexus is responsible for producing the cerebrospinal fluid (CSF) that is within the ventricles and surrounds the brain and spine1. These tumors are most commonly located in the lateral or fourth ventricles or the cerebellopontine angle from extension of the choroid plexus through the foramen of Luschka. Infratentorial locations are more common in adults, while in pediatric patients, supratenotrial locations are more common. Symptoms arise from increased intracranial pressure related to hydrocephalus such as headache, nausea, vomiting and craniomegaly. Other possible symptoms include seizure, subarachnoid hemorrhage and focal neurologic deficit such as hemiparesis, sensory deficits, cerebellar signs or cranial nerve palsy of the oculomotor (CN III), trochlear (CN IV) or abducens (CN VI) nerve. Hydrocephalus may be caused by overproduction of CSF, obstruction of CSF outflow by tumor or communicating hydrocephalus from blockage of CSF reabsorption by CSF-borne particulates.
Surgical resection is the choice of therapy for both benign and malignant lesions. Surgery can be complicated by tumor fragility and bleeding of the choroidal arteries. If gross total resection is not possible during the first procedure, a second and even third are recommended until complete resection is achieved, as five-year survival is 84%. In one study, recurrence rate following gross total resection was 9.6% and required repeat surgery2.
Malignant meningiomas are WHO grade III lesions characterized by anaplastic, papillary, or sarcomatous pathology. They have a greater recurrence risk than classic, benign meningiomas and typically more aggressive growth. They are characterized by cortical invasion and rapid recurrence following surgical resection. Frequent mitotic figures (≥4 mitoses per high-power field) or papillary features are strong pathological predictors of malignancy. Younger patients are more commonly affected. Surgical resection should be attempted and is first-line regardless of recurrence. Radiation therapy may be attempted if the patient is not a surgical candidate or declines surgical intervention after recurrence. These tumors may be bloody and steps including preoperative embolization of the arterial feeders should be taken to minimize blood loss in surgery, including early interruption of tumor blood supply during surgery prior to central debulking, dissection of the tumor capsule from the brain by dissecting and coagulating vascular and arachnoid attachments, and removal of attached bone and dura when possible. The Simpson grade establishes the extent of meningioma resection during surgery and correlates this with risk of symptomatic recurrence. Grade I entails complete removal with resection of underlying bone and associated dura. There is a 9% symptomatic recurrence at 10 years after resection. Grade II describes complete removal of the tumor and coagulation of the dural attachment. There is a 19% symptomatic recurrence at 10 years after resection. Grade III is complete removal without resection or coagulation of the dura, with 29% of patients experiencing symptomatic recurrence at 10 years after resection. Grade IV is subtotal resection, and 44% of patients have symptomatic recurrence at 10 years after resection. Finally, grade V is simple decompression with or without biopsy, and there is a 100% symptomatic recurrence at 10 years after surgery. Recently, the Simpson grading scheme has been called into question for different histological meningioma types. As convexity meningiomas tend to recur more rapidly than skull base meningiomas, Simpson grade I resection should be the goal22, meaning the goal is complete resection of the meningioma including its origin, attached dura and involved boned, in order to minimize future recurrence.
An ependymoma is a neoplasm originating from the ependymal cells lining the ventricular system of the CNS. In children, these tumors most commonly occur in the posterior fossa, usually originating from the part of the roof of the 4th ventricle called the inferior medullary velum whereas in adults, they are more common in the spine. Sixty-nine percent of intracranial ependymomas occur in pediatric patients with a mean age of 17.5 years across all patients. There are about 200 cases of pediatric intracranial ependymoma per year. Prognosis is worse with younger age. Ninety-six percent of intraspinal ependymomas occur in adults with a mean age of 40 years in all patients. Ependymomas can spread throughout the CNS via seeding through the CSF. Higher grade lesions are more likely to do this. WHO Grade I subtypes include myxopapillary ependymoma and subependymoma. WHO Grade II variants include cellular, papillary, clear cell and tanycytic (rare). WHO Grade III class ependymomas are anaplastic. Due to high propensity of seeding local metastasis, the entire spine needs to undergo diagnostic MRI to rule out drop-metastasis.
Intracranial ependymomas tend to be benign and most often occur in the floor of the 4th ventricle. As such, symptoms secondary to increased intracranial pressure due to hydrocephalus are most common, such as headache (80%), nausea and vomiting (75%), ataxia and vertigo (60%), seizures and cranial nerve palsies of the abducens (VI) and facial (VII) nerves. MRI is used for neuroimaging.
First-line treatment is neurosurgical intervention and gross total resection1. Lumbar puncture should be undergone 2 weeks following surgery to exclude seeding. Ependymomas are sensitive to radiation therapy, which can be administered postoperatively. Radiation therapy as an adjuvant to surgical resection increases 5-year survival from 20-40% to 40-80%. Adults fare better than children, with an 80% five-year survival compared with a 20-30% five-year survival in pediatric patients. Recurrence can occur at initial site of treatment following gross total resection. Seeding via CSF is another cause of treatment failure, occurring in 9-25% of patients.
Medulloblastomas are the most common pediatric brain malignancy, peaking in the first decade of life with a median age of diagnosis of 5-7 years. Girls have significantly better outcomes than boys. These tumors are embryonal in origin arising from neuroectodermal cells within the cerebellum. As they tend to arise in the cerebellar vermis and grow into the roof of the 4th ventricle, associated symptoms are generally related to hydrocephalus – headache, nausea, vomiting and ataxia. All medulloblastomas are classified as high grade or WHO grade IV, pathologically. Seeding throughout the neuroaxis is a problem, with 10-35% of patients presenting with seeding at diagnosis. Poor prognostic indicators include younger age (especially < 3 years), metastatic or disseminated disease, inability to perform gross-total resection (particularly with residual > 1.5 cm2) and histological differentiation along glial, ependymal or neuronal lines.
The treatment of choice for medulloblastoma is surgical debulking of the tumor to the greatest extent possible, followed by radiation therapy. Radiation to the whole craniospinal axis is necessary as the tumor has a high propensity to recur and spread via seeding. As the tumor is usually in a high risk location – the floor of the 4th ventricle, immediately adjacent to the facial colliculus in the pons – leaving residual is preferred to total resection to avoid neurologic deficit. Adjuvant chemotherapy may be used in patients with recurrent lesions or poorer overall outcomes. Commonly used agents are lomustine, cisplatin and vincristine. Up to 40% of patients with posterior fossa tumors may require permanent ventriculoperitoneal shunt following surgery.
Atypical Teratoid Rhabdoid Tumor (AT/RT)
This is an aggressive embryonal malignancy unique to the CNS. Infants and children are predominantly affected, with more than 90% of patients < 5 years of age, and most < 2 years. A minority of AT/RT are associated with primary renal rhabdoid tumor. There is a genetic relationship with deletion or monosomy of chromosome 22. Half of AT/RTs are located in the posterior fossa, particularly within the cerebellopontine angle. Thirty-three percent of patients have CSF seeding on presentation. Most die within 1 year of diagnosis.
Malignant Nerve Sheath Tumor
Malignant peripheral nerve sheath tumors – also known as malignant schwannomas, neurofibrosarcoma, and neurosarcoma – are a rare disease of the connective tissue surrounding nerves. There is a strong association with neurofibromatosis, especially type 1. Lifetime risk in patients with NF1 is estimated to be 8-13%. Symptoms of a malignant nerve sheath tumor include painless swelling of the extremities, difficulty moving an affected extremity, soreness, neurologic deficit, pain or sensory abnormality, dizziness, and balance problems.
Diagnosis is made using biopsy. First-line treatment is surgical excision with wide margins. Radiation therapy is usually undergone following surgery. Invasive tumors may require limb amputation. Chemotherapy is a possible adjuvant treatment. Thirty-nine percent of patients experience tumor metastasis, especially to the lung. Poor prognostic factors are large primary tumor (> 5 cm), high grade, neurofibromatosis, presence of metastasis, and young age.
Metastatic Brain Tumor
Metastases to the brain are the most common brain tumor. Imaging studies show that they comprise approximately 30% of cases. Unfortunately, 70% of these patients will have multiple lesions on imaging at the time of symptom onset. If only a solitary lesion is noted and the patient has a history of cancer, biopsy should be undergone as primary CNS tumor is more likely. The median survival with optimal treatment is 26-32 weeks, thus the aim of management is largely palliative1. Patients with neurologic symptoms have a median survival of 1 month without treatment. Other indications for resection are if the tumor is giving neurological compromise and/or if no primary tumor is present and the tumor needs to be resected for obtaining diagnosis. In our opinion, if the tumor is resectable, it is better to resect it than only obtaining a surgical biopsy, if surgical risks are reasonable.
The incidence of new cases of metastatic tumor in the U.S. has reached 170,000 annually. Most tumors spread hematogenously, but direct extension can occur. Cerebral metastases are in part due to lack of efficacy of most chemotherapeutic agents beyond the blood-brain barrier (BBB). Others can even weaken the BBB temporarily and promote CNS seeding.
The most common cancers with spread to the brain are lung cancer (44%), breast (10%), kidney – renal cell carcinoma (7%), GI tract cancers, especially colorectal cancers (6%), melanoma (3%), and undetermined source (10%).
Small-cell lung cancer is specifically most likely to metastasize to the CNS, with an 80% metastasis rate in patients with survival of 2 or more years after diagnosis. These tumors are highly radiosensitive and may be treated with radiation therapy with possible adjuvant chemotherapy.
Melanoma metastasis usually involves the pia and arachnoid meningeal layers. Surgical resection is first-line treatment, as these tumors are radioresistant. If gross total resection is not possible (i.e. > 4 metastases or inaccessible location), stereotactic radiosurgery and chemotherapy may be considered. Melanoma metastases are especially prone to bleed.
The most common tumors that metastasize to the brain in children are neuroblastoma, rhabdomyosarcoma, and Wilm’s tumor.
Signs and symptoms of metastatic disease are dependent on tumor location. Mass effect with large tumors or blockage of CSF drainage causing hydrocephalus results in symptoms due to increased intracranial pressure, including headache – present in 50%, the most common presenting symptom – and nausea and vomiting. Focal neurologic deficits due to compression of brain parenchyma or edema are also common. Seizures occur in 15% of patients. Mental status changes such as depression, lethargy, apathy, and confusion are also possible.
The typical workup of a patient with suspected metastasis to the brain is:
- CT of chest, abdomen, and pelvis with contrast to locate primary tumor
- Radionuclide bone scan (particularly in prostate, breast, kidney, thyroid, and lung cancers)
- Mammogram in women
- Prostate specific antigen (PSA) in men
- PET scan
- Taillibert S, Delattre JY. (2005). Palliative care in patients with brain metastases.Current Opinions in Oncology. 17(6): 588-592
- Vanuytsel LJ, Bessell EM, Ashley SE, Bloom HJ, Brada M. (1992). Intracranial ependymoma: long-term results of a policy of surgery and radiotherapy. International Journal of Radiation Oncology, Biology, and Physics. 23(2): 313-319.
- Mortazavi MM, Griessenauer CJ, Adeeb N, Deep A, Bavarsad Shahripour R, Loukas M, Tubbs RI, Tubbs RS. (2014). The choroid plexus: a comprehensive review of its history, anatomy, function, histology, embryology, and surgical considerations.Child’s Nervous System. 30(2): 205-214.
- Jeibmann A, Wrede B, Peters O, Wolff J, Paulus W, Hasselblatt M. (2007). Malignant progression in choroid plexus papillomas.Journal of Neurosurgery. 107: 199-202.
- Bierman PJ. (2014). Surgery for primary central nervous system lymphoma: Is it time for reevaluation? 28(7): 632-637.
- Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P. (2007). The 2007 WHO classification of tumours of the central nervous system.Acta Neuropathol. 114(2): 97-109.