Cancer Neurology
Eudocia Q. Lee
Patrick Y. Wen
PRIMARY BRAIN TUMORS
Background
Primary brain tumors (PBTs) are a heterogeneous group of neoplasms arising from the central nervous system (CNS) with varied outcomes and management strategies.
Epidemiology
1. A few more than 83,000 PBTs are diagnosed annually in the United States, of which approximately 25,000 are malignant.
2. There has been a steady rise in incidence of PBTs during the last two decades, in part because of increased sensitivity of imaging modalities.
3. The incidence of PBTs is 23.8/100,000 persons per year and varies significantly with age.
4. PBTs are the most common solid tumor in children and the leading cause of cancer death under the age of 19 years.
5. The most common tumor types (in decreasing order of frequency) are meningioma (38.3%), pituitary tumors (such as pituitary adenoma) (16.9%), glioblastoma (GBM) (14.5%), and nerve sheath tumors (such as vestibular schwannoma) (8.6%).
Genetic Factors
One percent to 5% of patients with brain tumors have an underlying genetic syndrome that increases their risk of developing a brain tumor (Table 9-1).
Table 9-1 Genetic Syndromes Associated With Brain Tumors | ||||||||||||||||||||||||||||||||||||||
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Environmental Factors
There are only two unequivocal risk factors for PBTs:
1. Cranial irradiation is associated with an increased risk for meningiomas (10-fold risk) and gliomas (three-to sevenfold risk) with a latency period of 10 to 20 years after exposure.
2. Immunosuppression is associated with an increased risk for CNS lymphoma.
3. The association between PBTs and other forms of radiation, such as electromagnetic radiation and radiofrequency radiation (from portable cellular phones with antenna) is less clear.
Pathophysiology
1. Gliomas arise from cells of neuroglial origin, whereas meningiomas arise from meningothelial (arachnoidal) cells.
2. Exact cell of origin in gliomas is uncertain, but there is increasing evidence that gliomas arise from neuroglial stem or progenitor cells.
Molecular Genetics
1. Familial syndromes account for less than 5% of CNS tumors. The genetic syndromes associated with brain tumors are listed in Table 9-1.
2. Brain tumors result from a multistep process driven by the sequential acquisition of genetic alterations. The accumulation of these genetic abnormalities results in uncontrolled cell growth and tumor formation.
3. The fifth edition of the World Health Organization (WHO) Classification of Tumors of the Central Nervous System (WHO CNS5), published in 2021, introduced major changes that advance the role of molecular diagnostics in CNS tumor classification.
4. Glioma: WHO CNS5 now divides gliomas into different families based on histology and molecular features:
a. Adult-type diffuse gliomas
1) Astrocytoma, isocitrate dehydrogenase (IDH)-mutant
a) WHO grade 2, 3, or 4
b) Mutation in IDH 1 or 2
c) Presence of CDKN2A/B homozygous deletion results in CNS WHO grade of 4, even in the absence of histologic features that characterize grade 4 (such as microvascular proliferation or necrosis)
2) Oligodendrogliomas, IDH-mutant, and 1p/19q co-deleted
a) Mutation in IDH1 or IDH2
b) Codeletion of chromosome arms 1p and 19q
c) Telomerase reverse transcriptase (TERT) promoter mutations
d) Mutations in the homolog of Drosophila capicua gene (CIC) or far-upstream binding protein 1 gene (FUBP1)
e) Notch1 mutations
3) Glioblastoma, IDH-wildtype
a) Presence of one of the following molecular abnormalities results in diagnosis, even in the absence of histologic features that characterize grade 4 (such as microvascular proliferation or necrosis)
TERT promotor mutations
Epidermal growth factor receptor (EGFR) gene amplification
Combined gain of entire chromosome 7 and loss of entire chromosome 10
b) Other receptor tyrosine kinase alterations, besides EGFR amplification, are common including phosphatase and tensin homolog (PTEN) deletion/mutation, phosphatidylinositol 3-kinase (PI3K) subunit mutations, platelet-derived growth factor receptor alpha (PDGFRA) amplification, and Neurofibromatosis type 1 (NF1) mutation
b. Pediatric-type diffuse low-grade gliomas
1) Diffuse astrocytoma, MYB- or MYB Proto-Oncogene Like 1 (MYBL1) altered
2) Angiocentric glioma
3) Polymorphous low-grade neuroepithelial tumor of the young (PLNTY)
4) Diffuse low-grade glioma, mitogen-activated protein kinase (MAPK) pathway-altered
c. Pediatric-type diffuse high-grade glioma
1) Diffuse midline glioma, H3 K27-altered
2) Diffuse hemispheric glioma, H3 G34-mutant
3) Diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype
4) Infant-type hemispheric glioma
5. Medulloblastoma: Four molecular subtypes characterized by one of the following:
a. Wingless (WNT) activated
b. Sonic hedgehog (SHH) activated and TP53-wildtype
c. SHH-activated and TP53-mutant
d. Non-WNT/Non-SHH
Prognosis
1. The prognosis of brain tumors is determined by tumor type, grade, and location and by patient’s age and functional status (Karnofsky performance status [KPS]).
2. As a result of this marked heterogeneity, the prognostic features and treatment options must be carefully reviewed for each patient.
3. The feasibility of resection is a key determinant of prognosis and depends on the location and the invasiveness of the neoplasm.
4. Histologic grade of the tumor is important and clearly dictates the survival, but care must be taken because sampling errors may underestimate the grade. Furthermore, low-grade neoplasms can transform to higher-grade neoplasms.
5. Advances in surgery, radiation therapy (RT), and chemotherapy have led to improvement in prognosis for some IDH-mutant gliomas and GBMs.
Diagnosis
Location
1. The frequency of tumors at a location depends on age and type of tumor.
2. In adults, 70% of tumors occur in cerebral hemispheres; and in children, 70% of tumors occur in posterior fossa.
Clinical Presentation
1. Symptoms are caused by a variety of effects caused by brain tumors including pressure against adjacent structures, elevated intracranial pressure (ICP), and seizures.
2. Symptoms can be acute or subacute but are generally progressive and depend on the size, location, and growth rate of tumor and peritumoral edema.
3. Acute symptoms can result from seizures, intratumoral hemorrhage, or rapid growth or edema in eloquent areas.
4. Among patients with new-onset seizures, 5% are found to have a brain tumor.
5. Generalized and focal seizures occur in 15% to 95% of patients with supratentorial tumors and are more common in low-grade tumors and meningiomas.
6. Can present with generalized or focal signs.
7. Increased ICP symptoms include change in mental status, headache, nausea, vomiting, drowsiness, and papilledema.
8. Headache is the presenting feature in 35% of patients and develops in up to 70% during the course of the disease. They are often indistinguishable from tension headaches or migraines. It should be borne in mind that the vast majority of headaches seen in unselected populations are benign. As headache is a nearly universal phenomenon, its actual relationship to tumor is often tenuous. They are usually bilateral, diffuse, and typically worsened with Valsalva maneuvers and lying down.
9. Focal signs include hemiparesis, sensory loss, ataxia, aphasia, memory loss, neglect, and visual loss.
Diagnostic Tests
1. Magnetic resonance imaging (MRI) enhanced with gadolinium is the imaging modality of choice for diagnosis of brain tumors.
2. Sometimes, computed tomography (CT) with contrast is the only choice in patients with pacemakers or metallic implants.
3. Tumor cells have been found in the peritumoral edema, which corresponds to the T2-weighted MRI abnormalities.
4. Other modalities such as magnetic resonance spectroscopy (MRS), perfusion and permeability imaging, positron emission tomography (PET), and single-photon emission computed tomography (SPECT) may be helpful in distinguishing tumor from radiation necrosis or inflammation.
5. Functional MRI can be used to define eloquent areas to assess the risk of surgery.
6. The presence of multiple lesions on a contrast-enhanced study favors a metastatic process, but metastases can present as a solitary lesion in up to 30% of patients and GBM can be multifocal in 13% of patients.
7. Lumbar puncture (LP) for routine cerebrospinal fluid (CSF) studies, cytology, and additional tests specific to tumor type is useful to rule out leptomeningeal involvement of tumors, especially in the case of lymphoma, medulloblastoma, pineal tumors, and germ cell tumors. LP is generally contraindicated if elevated ICP is suspected or if there are large mass lesions. Emerging technologies such as detection of genetic biomarkers from circulating tumor cells, circulating tumor DNA, extracellular vesicles, and microRNA may allow “liquid biopsy” from CSF.
8. In cases of suspected metastatic disease, a full workup to search for a primary tumor should be undertaken and includes ocular, testicular, breast (mammogram in females), and prostate examinations (males) and urinalysis, complete blood count, peripheral smear, stool guaiac testing, body CT, bone scan, and, increasingly, PET scan.
9. Stereotactic biopsy or craniotomy with resection of the mass allows histologic diagnosis and should be performed in most patients where diagnosis cannot be obtained otherwise.
Pathology
1. The classification, prognosis, and treatment of brain tumors are ultimately dependent on the histopathologic and molecular features of the surgical specimen and the clinical context.
2. Errors can occur when a small sample is taken for biopsy in a heterogeneous tumor and does not reflect the biology of the entire tumor.
3. Unlike other types of cancers, gliomas are not staged and instead classified according to grade. Glial tumors are graded on the basis of cellularity, nuclear atypia, mitoses, microvascular proliferation, necrosis, and molecular alterations according to the WHO system.
4. Grading for astrocytoma, IDH-mutant
a. WHO grade 2 astrocytoma shows relatively homogenous appearance, hypercellularity, nuclear atypia, and ill-defined tumor margins.
b. WHO grade 3 astrocytoma shows high cellularity, mitosis, and pleomorphism.
c. WHO grade 4 astrocytoma not only shows features of grade III but may also have necrosis, endothelial proliferation, or presence of CDKN2A/B homozygous loss.
Differential Diagnosis
1. A wide differential diagnosis must be kept in mind during the initial evaluation of a brain mass as many treatable conditions can mimic brain tumors.
2. The differential includes other PBTs, metastases, lymphoma, abscesses, viral infections, encephalomyelitis, demyelination, stroke, vascular anomaly, vasculitis, and granulomatous and inflammatory disease.
Treatment
Treatment of patients with brain tumors requires close cooperation of a multidisciplinary team of physicians including neurologists, neurosurgeons, radiation therapists, oncologists, neuroradiologists, neuropathologists, and psychiatrists.
Supportive Care
1. Corticosteroids
a. Used to reduce symptomatic vasogenic edema surrounding tumors, which lowers ICP and mass effect. Clinically, improvement begins within 12 to 48 hours with maximum improvement by fifth day.
b. Response is independent of type of corticosteroid used (dexamethasone, methylprednisolone, prednisone, hydrocortisone) in equivalent doses.
c. Dexamethasone is used widely because of low mineralocorticoid (salt-retaining) side effects.
d. Lowest dose of dexamethasone that achieves clinical benefit is generally recommended.
1) Steroids should be tapered to the lowest dose possible to avoid complications.
2) High doses of dexamethasone start with bolus of 10 mg IV and then 16 mg/d by mouth PO or IV.
3) Higher doses (up to 40 mg) can be given to critically ill patients until definitive treatment (eg, surgery) is undertaken.
4) Oral absorption is excellent.
5) Biologic half-life of oral dexamethasone is long enough for it to be given once or twice daily.
e. Side effects include glucose intolerance, oral candidiasis, opportunistic infections including Pneumocystis jiroveci pneumonitis (PJP), gastric irritation, adrenal suppression, steroid myopathy, osteoporosis, and psychiatric problems.
f. Patients may need glucose monitoring and H2 blockers or proton pump inhibitors to reduce gastric irritation.
g. Patients who are likely to remain on steroids for prolonged periods should have PJP prophylaxis (eg, 160 mg of trimethoprim plus 800 mg of sulfamethoxazole [Bactrim DS] 3 d/wk) and prophylactic therapy for osteoporosis (calcium and vitamin D supplements and bisphosphonates).
h. Patients who are on steroids may need adjustments to control edema perioperatively and during chemotherapy and radiation treatments.
2. Anticonvulsants
a. Prophylactic antiseizure medications (ASMs) are not recommended for patients unless they have history of seizures. There is no evidence that patients with brain tumors who have never had a seizure benefit from prophylactic anticonvulsants.
b. Prophylactic ASMs should be given to patients undergoing craniotomies but can be tapered off 1 to 2 weeks after the procedure if they have never had a seizure.
c. Cytochrome P450 enzyme-inducing antiepileptic drugs, such as phenytoin and carbamazepine, increase the metabolism of many chemotherapeutic agents and reduce their efficacy.
d. More than 20% of brain tumor patients receiving phenytoin or carbamazepine develop drug rashes.
e. ASMs such as levetiracetam, which do not induce cytochrome P450 enzymes, have less drug interactions and are better tolerated.
Prevention and Management of Venous Thromboembolism
Patients with brain tumors have an increased risk of developing venous thromboembolism (VTE) (20%-30% lifetime risk in patients with GBM). Extra care must be taken to prevent VTE in the perioperative period. When a patient develops VTE, anticoagulation is usually safe after the perioperative period and is more effective than inferior vena cava filtration devices. Low-molecular-weight heparin may be safer and slightly more effective than warfarin. Emerging data suggest that direct oral anticoagulants may also be safe and effective in brain tumor patients.
Supportive Care
Many patients with brain tumors benefit from physical and occupational therapy, psychiatric consultation, visiting nurses, social services, patient support groups, and brain tumor organizations (American Brain Tumor Association [2720 River Rd, Des Plaines, IL 60018, Phone: (773) 577-8750 or patient line: (800) 886-2282, e-mail: info@abta.org; www.abta.org]; the National Brain Tumor Society [55 Chapel Street, Suite 006, Newton, MA 02458, Phone: (617) 924-9997, www.braintumor.org]).
Therapy
Surgery
1. Decisions regarding aggressiveness of surgery for a PBT are complex and depend on the age and performance status of the patient; the feasibility of decreasing the mass effect with aggressive surgery; the resectability of the tumor (including the number and location of lesions), and, in patients with recurrent disease, the time since the last surgery.
2. Biopsy or surgical resection is performed on most patients to obtain pathologic confirmation of the type and grade of tumor and provides information on prognosis and treatment.
3. Biopsy is performed using stereotactic devices or intraoperative MRI. Biopsies are performed for tumors that are deep or in eloquent areas where surgical resection is contraindicated.
4. Because of heterogeneity in the tumor, a small biopsy sample may be nondiagnostic or not representative of the whole tumor.
5. Appropriate localization of biopsy to obtain the highest grade area is important.
6. Extensive tumor resection is the surgical procedure of choice for most tumors and improves neurologic function and survival. This can be achieved for many extra-axial tumors, but few intra-axial tumors can be resected completely.
7. Partial resection can be palliative by improving neurologic function and improving survival when total resection is not possible.
8. Repeated partial resections may be beneficial, especially for benign tumors.
9. Patients who develop hydrocephalus (usually because of tumors that obstruct the third or fourth ventricles) require a ventriculoperitoneal (VP) shunt to reduce ICP.
10. Some tumors such as brainstem gliomas have characteristic imaging features. Although pathologic confirmation is strongly preferred, biopsy is sometimes avoided in selected patients because of the high risk of neurologic deficits and patients might rarely be treated without tissue diagnosis.
11. Intraoperative MRI can help in clarifying normal and abnormal tissues, thereby allowing for more complete resection.
12. A postoperative MRI, with and without contrast, should be performed within 24 to 48 hours after surgery to document the extent of disease following surgical intervention.
Complications of Surgery
1. The standard risks of anesthesia and neurosurgery include hemorrhage, stroke, increased edema, direct injury to normal brain, infection, and VTE.
2. Postoperative cerebral hemorrhage may require evacuation if producing focal deficits.
3. Cerebral edema is usually present preoperatively and may be exacerbated during surgery by mechanical retraction, venous compression, brain manipulation, and overhydration. Generally, steroids are given for several days prior to craniotomy.
4. Risk of cranial infection is increased with length of operation and introduction of foreign materials (shunt tubing, clips, chemotherapy polymers), and most infections are caused by cutaneous and airborne pathogens. Most patients are given perioperative prophylactic antibiotics.
5. Communicating hydrocephalus can occur transiently postoperatively.
6. Neuroendocrine disturbances such as syndrome of inappropriate secretion of antidiuretic hormone can occur after surgery, and electrolytes and fluid balance should be carefully monitored to prevent hyponatremia and cerebral edema.
7. Surgery of the hypothalamic-pituitary axis can result in various degrees of panhypopituitarism and diabetes insipidus (DI).
RT
1. RT for patients with PBTs usually involves a limited field encompassing the tumor volume (commonly defined as the region showing T2-weighted abnormalities on an MRI scan plus a 1- to 2-cm margin).
2. Usual dose is 6,000 cGy for high-grade PBT such as GBM; 5,000 to 5,400 cGy for low-grade PBT such as astrocytoma, IDH-mutant, WHO grade 2 and 3,600 cGy for spinal tumors in 180- to 200-cGy fractions over approximately 6 weeks. A common scheme for whole brain radiation therapy (WBRT) in the management of brain metastases (BMs) is 3,000 cGy in 10 to 15 fractions.
3. Several different treatment approaches are used to treat brain tumors including conformal external beam (most common), stereotactic radiosurgery (SRS), and stereotactic radiotherapy (SRT).
4. Increasingly sophisticated techniques are available to administer conformational irradiation, including intensity-modulated radiation therapy, which allows variation of radiation dose in different parts of the radiation field.
5. SRS involves the treatment of small intracranial targets (such as BMs) using a large, single fraction of ionizing radiation in stereotactically directed narrow beams. It allows a high dose of radiation to be delivered to the tumor while relatively sparing surrounding brain. SRS can be administered using x-rays from stereotactic linear accelerators, γ-irradiation from cobalt sources in Gamma Knife radiosurgery, and protons from cyclotrons (proton beam therapy). Radiation necrosis can occur months and even years later. Risk increases with dose and volume treated; 5% to 10% of patients require surgical resection of necrotic area for symptomatic relief.
6. SRT is stereotactic radiation administered in multiple fractions to reduce risk of radiation injury to surrounding structures. It tends to be used for larger tumors.
Chemotherapy
1. The blood-brain barrier (BBB) provides the CNS with a privileged environment and consists of the cerebrovascular-capillary endothelium. Only physiologically small, lipid-soluble drugs or actively transported drugs can cross the BBB.
2. Chemotherapy is useful for primary central nervous system lymphoma (PCNSL), oligodendroglioma, astrocytoma, and medulloblastoma. Temozolomide has modest efficacy in GBM.
NEUROEPITHELIAL TUMORS
Pilocytic Astrocytoma
Background
1. The most common circumscribed astrocytic gliomas in childhood.
2. Mainly in children and adolescents but 25% occur in patients older than 18 years.
3. Also seen in individuals with neurofibromatosis type 1 (NF1).
Pathophysiology
1. Associated with MAPK alterations, notably KIAA1549:BRAF tandem duplication and fusion.
2. Mostly sporadic, but deletions of 17q (NF1) are associated with 15% of optic gliomas in patients with NF1.
Prognosis
1. Indolent course, often surgically resectable, and rarely transforms to malignant tumor.
2. Greater than 90% 10-year survival for supratentorial lesions after total resection.
3. A 95% 25-year disease-free survival for cerebellar pilocytic astrocytoma after total resection.
4. A 74% to 84% 10-year survival for subtotal resection.
5. In children, 75% stable at 4-year follow-up after surgery and chemotherapy when too young to receive radiation.
Diagnosis
Location
1. In children, it occurs in the cerebellum, optic pathway, and hypothalamus.
2. In young adults, it arises in cerebrum, brainstem, optic nerve, thalamus, and hypothalamus.
Clinical Presentation
Clinical features depend on location. Cerebellar lesions produce symptoms secondary to obstruction of CSF flow or pressure on cerebellum leading to headaches and ataxia.
Diagnostic Tests
MRI with gadolinium typically shows a cyst with mural nodule that enhances a nodule alone.
Pathology
1. WHO grade I, grossly well-circumscribed, and gelatinous appearance.
2. Two microscopic patterns: A tightly packed parallel array of well-differentiated astrocytes with Rosenthal fibers (globular, refractile, homogenous, eosinophilic bodies) and a loose matrix of astrocytes, long slender piloid “hairlike” cells, and amphophilic granular bodies.
3. Diagnosed by means of classical histopathology or by a low-grade piloid astrocytic neoplasm with a solitary MAPK alteration, such as KIAA1549:BRAF tandem duplication and fusion.
Differential Diagnosis
Other types of circumscribed astrocytic gliomas such as pilocytic astrocytoma with histological features of anaplasia; astrocytoma, IDH-mutant; dysembryoplastic neuroepithelioma (DNT); ependymoma; and ganglioglioma.
Treatment
1. Some tumors in surgically inaccessible areas (eg, optic nerve glioma) grow very slowly and may be observed for many years before definitive therapy is required.
2. Surgically curable if complete resection is possible.
3. Conformal radiation or SRT is helpful if resection is not possible or for recurrent tumor.
4. Chemotherapy with agents such as carboplatin and vincristine is useful in young children.
5. For tumors with MAPK alterations, therapies targeting the MAPK pathway such as MEK inhibitors are under investigation.
Pleomorphic Xanthoastrocytoma
Background
Rare circumscribed astrocytoma with characteristic clinical, imaging, and pathologic features.
Pathophysiology
1. Believed to originate from subpial astrocytes because of its superficial location with attachment to the leptomeninges.
2. BRAF (V600E) mutations occur in approximately 60% of PXAs.
Prognosis
1. Indolent lesions.
2. Good with resection, 76% 10-year survival.
3. Rare anaplasia (15%-20% of patients) associated with poor prognosis.
Diagnosis
Location
Predilection for superficial temporal and parietal lobes involving the leptomeninges and, rarely, the dura.
Clinical Presentation
1. Most common in children and young adults (second and third decades of life).
2. Usually have a long history of seizures before diagnosis.
3. Occasionally causes headaches and focal deficits.
Diagnostic Tests
MRI shows a heterogenous, superficial meningocerebral nodule, often associated with a cyst, iso- to hypointense on T1-weighted images and enhancing.
Pathology
1. Typically WHO grade 2; enlarged, lipid-laden astrocytes; inflammation; extreme pleomorphism; cellular atypia; and spindle and multinucleated giant cells. No necrosis or vascular hyperplasia.
2. Undergoes transformation to WHO grade 3 in 15% to 20% of patients.
Differential Diagnosis
Can be mistaken histologically for fibrous histiocytoma of the meninges, giant cell astrocytoma with histiocytic infiltration, and lipidized giant cell GBM multiforme. Must also be differentiated from other forms of gliomas and dysembryoplastic neuroepithelial tumor (DNT).
Treatment
1. Surgical resection.
2. RT and chemotherapy may be considered for recurrent tumor.
Subependymal Giant Cell Astrocytoma or Subependymal Giant Cell Tumor
Background
1. Rare, benign, slow-growing glioneuronal tumor that usually arises in periventricular areas.
2. Found in children and young adults.
3. Almost exclusively associated with tuberous sclerosis complex (TSC) and present in 5%-20% of patients with TSC.
Pathophysiology
1. Associated with neurocutaneous disorders such as TSC and nevus sebaceous syndrome.
2. Partial loss of chromosome 22q.
Prognosis
1. Slow growing and benign.
2. Rarely malignant degeneration.
Diagnosis
Location
Arises in the wall of the lateral ventricle, attached to caudate head.
Clinical Presentation
1. Often diagnosed incidentally in TSC patients as part of surveillance.
2. May obstruct CSF flow at the foramen of Monro and cause obstructive hydrocephalus producing headache and visual disturbance.
Diagnostic Tests
1. MRI shows an intraventricular enhancing mass.
Pathology
1. WHO grade 1, giant astrocytes with glassy, eosinophilic cytoplasm, without significant anaplasia. May express neuronal markers.
2. Lesion represents neoplastic transformation of “candle guttering” subependymal nodules in TS.
Differential Diagnosis
Choroid plexus tumors, ependymoma, subependymoma, and astrocytoma.
Treatment
1. Surgical debulking for symptomatic (especially obstructive symptoms) or growing lesions. Complete resection may be curative.
2. Mechanistic target of rapamycin (mTOR) inhibitor everolimus is FDA-approved for TSC-associated SEGA.
3. Occasional role for SRS or SRT.
Astrocytoma, IDH-Mutant
Background
1. Diffusely infiltrating gliomas harboring a mutation in either IDH1 or IDH2 genes with absence of 1p and 19q codeletion and frequent inactivating mutations in ATRX and TP53 genes
2. CNS WHO grade 2, 3, or 4 depending on histological and molecular features
3. Lower grades gradually evolve to higher grades, ultimately causing morbidity and reduced survival.
Epidemiology
1. Incidence rate is 0.5/100,000 and peaks in the third and fourth decades.
2. Mostly occur in young adults.
Pathophysiology
1. Usually sporadic.
2. Associated with characteristic molecular abnormalities including mutations in IDH1 or IDH2, TP53, and ATRX (see “Molecular Genetics” section).
Prognosis
1. All lower-grade astrocytomas eventually progress to higher-grade tumors.
2. Astrocytoma, IDH-mutant, WHO grade 2, associated with a median survival of 10 to 12 years.
3. Astrocytoma, IDH-mutant, WHO grade 3, associated with a median survival of 8 to 10 years.
4. Astrocytoma, IDH-mutant, WHO grade 4, associated with a median survival of 3 to 4 years.
Diagnosis
Clinical Presentation
1. Grade 2 astrocytomas usually present with new-onset seizures (50%-70%). Less commonly, they present with headaches, focal deficits, or subtle neurobehavioral changes. Some patients may be asymptomatic.
2. Grade 3 or 4 astrocytomas often present with symptoms of increased ICP (headache, nausea, vomiting), seizures, or focal neurologic findings related to the size and location of the tumor and associated peritumoral edema.
Diagnostic Tests
1. MRI in grade 2 astrocytoma typically shows a nonenhancing white matter mass, hypointense T1, hyperintense T2, and fluid-enhanced inversion recovery (FLAIR) with ill-defined borders and little or no edema. A subset may be characterized by T2/FLAIR mismatch: fairly homogeneous hyperintensity on T2 and relative central hypointensity with a rim of hyperintensity on FLAIR.
2. MRI in grade 3 or 4 astrocytoma can show T2-FLAIR hyperintense lesions with vasogenic edema, mass effect, and variable enhancement.
3. Pathologic diagnosis ultimately depends on obtaining tissue via biopsy or surgical resection.
Pathology
1. IDH-mutation required for diagnosis
2. Retention of 1p and 19q, along with ATRX and TP53 mutations, help distinguish astrocytoma, IDH-mutant, from oligodendroglioma.
3. WHO grade 2 (formerly known as low grade): mild nuclear atypia, increased cell density
4. WHO grade 3 (formerly known as anaplastic): increased mitosis
5. WHO grade 4 (formerly known as glioblastoma, IDH-mutant): vascular proliferation, necrosis, or CDKN2A/B loss
6. Biopsy results can be misleading because gliomas often have varying degrees of cellularity, mitoses, or necrosis from one region to another.
Differential Diagnosis
Includes glioblastoma, oligodendroglioma, ganglioglioma, DNT, infarction, demyelination, progressive multifocal leukoencephalopathy, and vasculitis.
Treatment
1. Treatment depends on WHO grade, molecular features, and prognostic factors.
2. Maximal safe resection of tumor improves neurologic deficits and results in prolongation of survival.
3. For select patients with grade 2 astrocytoma (such as age <40 years who undergo complete resection), observation with serial imaging until progression may be a reasonable approach.
4. For grade 2 astrocytoma, requiring treatment, options may include radiation combined with systemic therapy or systemic therapy alone.
a. Involved field RT is a standard component of treatment, which may ameliorate symptoms, improve survival, and reduce seizure frequency in grade 2 astrocytoma.
b. Timing of irradiation (upfront after surgery vs at recurrence) is controversial. Upfront irradiation delays recurrence, but overall, survival similar to patients who do not receive irradiation until there is evidence of recurrent disease.
c. Patients with a greater likelihood of rapid disease progression (age ≥40 years, incomplete resection) may benefit from upfront treatment.
d. Radiation combined with chemotherapy may be beneficial in select “high-risk” grade 2 astrocytoma patients (age ≥40 years and/or incomplete resection). In this select subgroup, RT followed by procarbazine, lomustine (CCNU), and vincristine (PCV) was associated with longer overall survival compared to RT alone (13.3 vs 7.8 years). This study was performed prior to U.S. FDA approval of temozolomide so unclear if combining RT with temozolomide would have similar results.
e. Benefit for IDH inhibitor vorasidenib over placebo in extending progression-free survival and delaying time to next intervention in patients with residual or progressive disease after surgery.
5. For grade 3 astrocytoma, recommended upfront treatment includes radiation and temozolomide. Results from an international, phase III randomized trial (CATNON) of 1p/19q nondeleted grade 3 gliomas suggest survival benefit with the addition of adjuvant temozolomide to radiation but not concurrent temozolomide.
6. For grade 4 astrocytoma, standard of care is not yet established. One option is to treat patients with regimens similar to glioblastoma: radiation + concurrent temozolomide followed by adjuvant temozolomide.
Oligodendroglioma, IDH-Mutant and 1p/19q Co-Deleted
Background
1. Diffuse gliomas characterized by mutations in IDH1 or IDH2 and loss of chromosomes 1p and 19q (1p/19q codeletion).
2. Approximately 1,000 oligodendrogliomas are diagnosed in the US every year.
3. Most occur between ages 25 to 50 years, men more often than women.
Pathophysiology
1. Cell of origin is unknown but believed to arise from glial precursor cells.
2. IDH mutation is likely initiating event followed by 1p/19q loss.
Prognosis
1. More favorable prognosis compared astrocytoma, IDH-mutant.
2. Deletions in 1p and 19q associated with sensitivity to chemotherapy and radiotherapy.
3. Grade 2 Oligodendroglioma: Median survival is 10 to 15 years.
4. Grade 3 Oligodendroglioma: Median survival is 5 to 9 years.
Diagnosis
Location
Typically supratentorial with frontal lobe most common.
Clinical Presentation
Usually present with seizures; occasionally headaches, focal deficits, or personality changes depending on tumor location and rate of growth.
Diagnostic Tests
1. For oligodendroglioma, WHO grade 2, MRI generally shows a nonenhancing, T2-FLAIR hyperintense lesion with mass effect. Calcifications can be seen in 50% to 90%. May be well demarcated, located near cortical surface, with little or no edema; cystic (20%); hemorrhage (10%).
2. Oligodendroglioma, WHO grade 3, may demonstrate enhancement.
3. Pathologic diagnosis ultimately depends on obtaining tissue via biopsy or craniotomy.
Pathology
1. IDH mutation and 1p/19q loss required for diagnosis.
2. CNS WHO grade 2 (formerly known as low grade): grossly soft, grayish-pink tumors frequently with calcifications, hemorrhages, cysts, delicate vessels. Microscopically round nuclei with perinuclear halo (“fried-egg” appearance in paraffin), delicate branching vessels (“chicken wire” vasculature), calcification, perineuronal satellitosis (secondary structures of Scherer).
3. CNS WHO grade 3 (formerly known as anaplastic): high cellularity, increased mitotic rate, pleomorphism, microvascular proliferation, and occasional necrosis.
4. CNS WHO grade 2 oligodendrogliomas eventually progress to CNS WHO grade 3.
5. TERT promoter mutations are common but ATRX mutations and TP53 mutations are rare, molecular features that can help distinguish oligodendroglioma from astrocytoma, IDH-mutant.
Differential Diagnosis
Oligodendroglioma must be differentiated from astrocytoma, ganglioglioma, DNT, and GBM.
Treatment
1. Treatment may depend on grade, molecular features, and prognostic factors.
2. Maximal safe resection of tumor improves neurologic deficits and quality of life and results in prolongation of survival.
3. Oligodendroglioma, WHO grade 2 (treatment recommendations similar to astrocytoma, IDH-mutant, WHO grade 2)
a. For select patients (such as age <40 years who undergo complete resection), observation with serial imaging until progression may be a reasonable approach.
b. For those requiring treatment, options may include radiation combined with systemic therapy or (in selected cases) systemic therapy alone.
c. For “high-risk” oligodendroglioma (age ≥40 years and/or incomplete resection), the addition of PCV chemotherapy to RT extends survival over RT alone.
d. Benefit for IDH inhibitor vorasidenib over placebo in extending progression-free survival and delaying time to next intervention in patients with residual or progressive disease after surgery.
4. Oligodendroglioma, WHO grade 3
a. For patients with 1p/19q codeleted tumors, two large randomized trials demonstrated a survival benefit with RT and PCV compared to RT alone.
b. The international, phase III, randomized CODEL study compares radiation + PCV versus radiation + temozolomide in 1p/19q codeleted grade 3 oligodendrogliomas and high-risk grade 2 oligodendroglioma. Results are pending.
Glioblastoma, IDH-Wildtype
Background
1. GBMs are the most common malignant PBT.
2. Incidence rate is 3 to 4/100,000.
3. Peak age incidence is 60 years.
4. Male-to-female ratio is 3:2.
Pathophysiology
1. Usually sporadic.
2. Believed to arise from neuroglial stem or progenitor cells.
3. Characterized by molecular heterogeneity.
Prognosis
1. Uniformly fatal despite aggressive therapy. Occasional long-term survivors.
2. Factors that portend a poor prognosis: Older age, less than gross total resection, poor functional status (KPS < 70).
3. Median overall survival with maximal therapy is 15 to 18 months.
Diagnosis
Location
Cerebral hemispheres, especially frontal (40%) and temporal (30%) lobes, and rarely in adults’ brainstem, cerebellum, and spinal cord.
Clinical Presentation
1. Patients often present with symptoms of increased ICP (headache, nausea, vomiting), seizures, or focal neurologic findings related to the size and location of the tumor and associated peritumoral edema.
2. Can have symptoms for several months with GBM.
Diagnostic Tests
1. CT and MRI can show heterogeneous enhancing lesions with vasogenic edema, mass effect, and frequently, tracks along white matter paths including the corpus callosum (butterfly glioma). Occasionally have associated hemorrhage or calcification. GBM usually also has ring enhancement and central necrosis.
2. MRS shows elevated choline peaks (reflecting active membrane synthesis) and decreased N-acetyl aspartate peaks (reflecting neuronal loss).
3. Histologic diagnosis ultimately depends on obtaining tissue via biopsy or craniotomy.
Pathology
1. WHO grade 4.
2. Histologically characterized by pseudopalisading areas of necrosis, endothelial vascular proliferation, pleomorphism, and mitosis.
3. Molecular characteristics include IDH-wildtype, TERT promoter mutation, +7/−10 copy number changes, EGFR amplification.
4. Histologic variants include giant cell glioblastoma, gliosarcoma, and epithelioid glioblastoma (characterized by BRAF V600E mutation).
Differential Diagnosis
Includes other PBTs, metastases, lymphoma, and abscess.
Treatment
Surgery
1. Maximal safe resection of tumor improves neurologic deficits and quality of life and results in modest prolongation of survival.
2. The extent of tumor debulking should be documented with an immediate postoperative MRI scan performed with and without contrast.
3. Not curative even with apparent gross total resection as infiltrative microscopic disease inevitably remains in surrounding brain.
4. If resection is not possible because the tumor is in eloquent area, it should be biopsied to obtain histologic diagnosis. Every effort should be made to obtain tissue from area of actively growing tumor (usually enhancing area) to avoid undersampling. PET and perfusion MRI may help direct biopsy.
Radiation Therapy
1. Involved field RT is a standard component of treatment. Ameliorates symptoms and improves survival.
2. Typical RT dosing is 60 Gy in 2 Gy fractions, although hypofractionated RT (eg, 40 Gy in 15 fractions) is noninferior in patients aged >65 to 70 years of age.
3. Because RT can produce additional BBB dysfunction, corticosteroid requirements may increase and scans may look worse during the first 3 months after completion of RT (especially when RT was combined with chemotherapy), although there is no actual tumor progression (pseudoprogression).
4. Despite RT, most tumors recur within 2 cm of the original tumor site.
5. Repeat radiation is considered in special circumstances.
6. Other radiotherapy methods such as brachytherapy, hyperfractionation, radiosurgery, and radiosensitizers have not significantly improved survival.
Chemotherapy
1. In newly diagnosed GBM, the standard of care is radiation combined with temozolomide (an alkylating agent).
a. Overall, the addition of temozolomide produces a modest increase in median survival and a small increase in percentage of long-term survivors. Benefit greater for patients with methylation of the methylguanine DNA methyltransferase (MGMT) gene promoter.
b. Temozolomide is given concurrently with RT (75 mg/m2 p.o. daily during RT), followed by 4 weeks off treatment, and then adjuvantly as 150 to 200 mg/m2 p.o. days 1 through 5 every 28 days for six cycles. Toxicities include nausea, fatigue, and marrow suppression. Use of prolonged low-dose
temozolomide increases risk of PJP. Patients receiving this regimen often receive PJP prophylaxis.
c. The addition of tumor treating fields (a locoregionally delivered antimitotic treatment worn as a device on patient’s head) to adjuvant temozolomide after radiation may modestly extend survival over standard of care.
2. In patients aged 18 to 70 year with MGMT methylated GBM, an open label, randomized, phase 3 trial suggested that RT combined with six 42-day cycles of lomustine (CCNU) 100 mg/m2 p.o. on day 1 + temozolomide 100 mg/m2 p.o. on days 2 to 6 might improve survival over standard of care RT + temozolomide, although toxicity may be higher.
3. Studies performed before temozolomide became the standard of care showed that slow-release polymer wafers impregnated with BCNU (Gliadel wafers) placed in the wall of the surgical cavity at the time of debulking improves survival in newly diagnosed and recurrent GBM by approximately 2 months. BCNU wafers have largely fallen out of favor because temozolomide became standard of care.
4. For recurrent GBM, options include lomustine or bevacizumab.
a. Bevacizumab is a humanized monoclonal antibody that binds vascular endothelial growth factor (VEGF). May have antitumor activity and helps reduce peritumoral edema and corticosteroid use. Standard dose is 10 mg/kg intravenously every 2 weeks. Toxicities include hypertension, proteinuria, and rarely serious hemorrhage (including CNS) and thromboembolism (including stroke, deep vein thrombosis [DVT], pulmonary embolism [PE]). Studies of bevacizumab have not demonstrated a survival benefit compared to lomustine. Retrospective data and anecdotal evidence suggest that bevacizumab improves quality of life in part because of its steroid-sparing effects.
b. Lomustine (CCNU) is an alkylating agent and is dosed as 90 to 130 mg/m2 p.o. once every 6 weeks for six cycles total. Toxicities include nausea, fatigue, and marrow suppression (more severe than temozolomide).
Experimental Therapies
Targeted molecular therapy (eg, inhibitors various signal transduction molecules), viral gene therapy, tumor vaccines (dendritic and peptide), immunotherapy, and inhibitors of tumor invasion are being evaluated in clinical trials.
Diffuse Midline Glioma, H3 K27-Altered
Background
1. WHO grade 4 gliomas (mostly astrocytic differentiation) that arise in the midline (eg, pons, thalamus, cerebellum, spinal cord) and characterized by global hypomethylation of histone H3 at lysine 27 (H3K27me3).
2. Mostly seen in children but can be seen in adults.
3. Diffuse midline gliomas represent 10% to 15% of all pediatric PBTs and are the leading cause of brain-tumor-related deaths in children.
Pathophysiology
1. Cell of origin likely resides in the ventral pons but specific cell of origin remains unclear.
2. Epigenetic dysregulation plays an important role in pathogenesis.
Prognosis
Diffuse midline glioma has a poor prognosis with a median survival of only 1 year despite aggressive therapy.
Diagnosis
Clinical Presentation
Presentation depends on tumor location. Symptoms may include cranial nerve (CN) palsies, ataxia, weakness, numbness, and hydrocephalus.
Pathology
1. WHO grade 4.
2. Usually astrocytic in origin.
3. Characterized by global hypomethylation of histone H3 at lysine 27 (H3K27me3), driven by mutations in H3 genes including, HIST1H3B/C (H3.1K27M) or H3F3A (H3.3K27M), or through overexpression of enhancer of zeste homolog inhibitory protein in patients harboring wildtype H3.
4. High-grade features, such as mitotic activity, microvascular proliferation, and necrosis, may be seen but are not necessary for the diagnosis.
Differential Diagnosis
Includes astrocytoma, ependymoma, medulloblastoma, vascular malformation, cysticercosis, encephalitis, tuberculoma, multiple sclerosis, postinfectious encephalomyelitis, or gliosis.
Treatment
1. Surgical resection often limited due to tumor’s location and infiltrative nature.
2. Biopsy (open or CT-guided stereotactic) is indicated when the diagnosis of diffuse midline glioma is in doubt.
3. Treatment for diffuse brainstem glioma is RT (54-56 Gy in daily fractions of 1.8-2.0 Gy).
4. VP shunt may be necessary for obstructive hydrocephalus.
5. Chemotherapy with temozolomide, PCV, carboplatin of limited benefit.
Ependymal Tumors
Background
1. Ependymomas are tumors derived from ependymal cells that line the ventricular surface.
2. Ependymomas are classified based on histopathology, location, and molecular features with typical signatures related to anatomic site.
a. Supratentorial (ST) tumors
1) ZFTA (zinc finger translocation-associated): mostly occur in young children but can be seen in adults.
2) YAP1 (Yes-associated protein 1) fusion-positive: mostly occur in infants.
3) NEC (not elsewhere classified): no pathogenic gene fusion of ZFTA or YAP1 can be detected.
4) NOS (not otherwise specified): molecular testing not feasible or successful.
b. Infratentorial [PF (posterior fossa)] tumors
1) PF group A (PFA): absent histone H3 K27-trimethylation, poor prognosis, mostly occur in infants and young children.
2) PF group B (PFB): present histone H3 K27-trimethylation, mostly occur in adolescents and adults, comparably better prognosis than PFA.
3) NEC
4) NOS
c. Spinal (SP) tumors
1) Spinal ependymoma: mostly adults, no morphologic features of myxopapillary ependymoma or subependymoma, frequently associated with 22q loss (where NF2 located).
2) Spinal ependymoma, MYCN-amplified: poor prognosis with rapid progression, frequent leptomeningeal dissemination, and poor response to treatments.
3) Myxopapillary ependymoma: mostly adults, arise from the conus medullaris and filum terminale of the spinal cord, classified as WHO grade 2, good outcomes.
4) Subependymoma: slow-growing benign lesions that often do not require treatment and are classified as WHO grade 1.
Epidemiology
1. Comprises 2% to 8% of all PBTs, 6% to 12% of intracranial gliomas in children (intracranial ependymoma less common in adults), and 60% of spinal cord gliomas (most common spinal cord glioma in adults).
2. In children, ependymomas are the most common intraventricular tumor and often arise in the fourth ventricle.
3. In adults, 65% of ependymomas arise within the spinal cord.
Pathophysiology
1. Genomic alterations vary according to tumor location.
2. Posterior fossa ependymoma group A is characterized by loss of nuclear expression of trimethylation of the lysine residue at position 27 on the histone protein (H3K27me3).
3. Supratentorial ependymomas with ZFTA fusion harbor an oncogenic fusion between ZFTA (previously known as C11orf95) on chromosome 11 and another gene (most commonly RELA but can have other partners such as MAML2/3, NCOA1/2, MN1, or CTNNA2).
4. Supratentorial ependymomas with YAP1 fusion typically harbor YAP1-MAMLD1 fusions.
Prognosis
1. Subependymoma is indolent and often does not require treatment other than surgical resection.
2. Intracranial ependymoma in children is associated with poor long-term survival with 10-year survival rates of 50% to 70%.
3. Spinal cord ependymoma, mostly diagnosed in adults, are typically slow growing tumors with 10-year overall survival more than 90%.
4. Posterior fossa ependymoma group A and spinal ependymoma MYCN-amplified are poor prognostic subtypes.
Diagnosis
Location
1. Ependymomas are most frequently located in the brain in children and in the spine in adults.
2. Myxopapillary ependymomas most commonly involve lumbosacral spinal cord and filum terminale.
3. Ependymomas may spread via CSF in approximately 10%. Metastatic spread outside the CNS is rare.
Clinical Presentation
1. Intracranial tumors produce symptoms because of obstruction of CSF flow (headaches, nausea, vomiting, visual disturbance), ataxia, dizziness, hemiparesis, and brainstem symptoms.
2. Spinal cord tumors present as a chronic, progressive myelopathy, or cauda equina syndrome.
Diagnostic Tests
1. Intracranial ependymomas on MRI demonstrate a well-demarcated, heterogenous, enhancing intraventricular mass, with frequent calcifications. Obstructive hydrocephalus and hemorrhage may be present.
2. Intramedullary spinal cord ependymomas on MRIs may appear as a widened spinal cord with heterogeneous enhancement and peritumoral edema. Unlike intracranial ependymomas, calcifications are rare.
3. Myxopapillary ependymomas on MRI demonstrate a well-demarcated, ovoid, contrast enhancing mass in the cauda equina/conus/filum terminale region.
4. Extent of disease evaluation should include MR imaging of the entire CNS axis and CSF evaluation to rule out neuraxis dissemination.
Pathology
1. Subependymoma, WHO grade 1, is a benign lesion located within ventricles. Mostly diagnosed in adults.
2. Myxopapillary ependymoma, WHO grade 2, is a glioma with papillary architecture and perivascular myxoid change found mostly in the conus medullaris and filum terminale of the spinal cord. Mostly diagnosed in adults.
3. Ependymoma, WHO grade 2, is grossly well-demarcated and is microscopically densely cellular with ependymal rosettes, blepharoplasts, and perivascular pseudorosettes. It arises from the wall of the ventricle or from the spinal canal.
4. Ependymoma, WHO grade 3, has malignant features such as mitotic activity, pleomorphism, and necrosis.
Differential Diagnosis
Other types of PBTs including medulloblastoma, pilocytic astrocytoma, and choroid plexus tumors in the posterior fossa. Differential diagnosis of spinal cord tumors include astrocytoma, cavernous malformation, diffuse midline glioma, and transverse myelitis.
Treatment
1. Gross total resection, when feasible, is optimal treatment.
2. For intracranial ependymoma, management depends on age, extent of resection, and location of disease. Postoperative RT and/or chemotherapy is often needed due to risk of recurrence and dissemination.
3. For spinal cord ependymoma, postoperative RT is recommended following incomplete resection and for WHO grade 3 tumors.
4. Craniospinal radiation reserved for tumors with CSF spread.
5. Chemotherapy is used in children younger than 1 year to delay onset of RT.
Choroid Plexus Tumors
Background
1. Choroid plexus tumors are derived from the choroid plexus epithelium.
2. Peak incidence in the first two decades of life although can be seen in adults.
3. Accounts for less than 1% of all intracranial tumors.
4. Choroid plexus papillomas (CPPs) are benign and account for 60% of choroid plexus tumors.
Pathophysiology
1. CPP, WHO grade I, histologically resembles normal choroid plexus and probably represents local hamartomatous overgrowths. CPP with increased mitotic activity are WHO grade 2.
2. Choroid plexus carcinoma (CPC), WHO grade 3, is an aggressive tumor with dense cellularity, mitoses, nuclear pleomorphism, focal necrosis, loss of papillary architecture, and invasion of neural tissue. They frequently seed CSF pathways. Usually occurs in children younger than 8 years. Associated with Li-Fraumeni syndrome (because of mutations in p53).
Prognosis
1. Good with CPP. With complete resection, 80% 5-year survival; 4.3% recurrence rate overall. Malignant transformation to CPC is rare.
2. Poor with CPC, 40% 5-year survival rate.
Diagnosis
Location
1. In adults, common in lateral ventricle (50%), fourth ventricle (40%), and third ventricle (5%).
2. In children, most common in lateral ventricles and cerebellopontine angle (CPA).
Clinical Presentation
Present with symptoms secondary to CSF obstruction or CSF overproduction, headaches, nausea, vomiting, ataxia.
Diagnostic Tests
1. With CPPs, MRI shows a homogenous, enhancing mass with prominent flow voids caused by rich vascularization, frequent calcification.
2. With CPCs, enhancement is more heterogeneous with necrosis and brain parenchymal invasion.
Differential Diagnosis
Ependymoma, astrocytoma, and metastases.
Treatment
1. Extent of surgical resection is an important predictor of survival.
2. RT at recurrence for CPP.
3. For CPC, chemotherapy and radiation may be associated with better survival although there is no consensus.
Neuronal and Glioneuronal Tumors
Background
1. Rare tumors characterized by variable amount of neuronal differentiation.
2. Include various subtypes including ganglioglioma, gangliocytoma, dysembryoplastic neuroepithelial tumor (DNT), neurocytoma, and dysplastic cerebellar gangliocytoma (Lhermitte-Duclos disease).
Epidemiology
1. Occur in children and young adults in the first three decades of life.
2. Account for less than 1% of glial neoplasms.
3. Neurocytomas occur in patients aged 20 to 40 years.
4. Lhermitte-Duclos disease is an extremely rare.
Pathophysiology
1. Gangliogliomas associated with Down syndrome, callosal dysgenesis, and neuronal migration disorders. Up to 60% will harbor a BRAF V600E mutation.
2. Lhermitte-Duclos disease can be sporadic or familial (may occur as part of Cowden disease, characterized by mucosal neuromas and breast cancer, an autosomal dominant disorder caused by germline mutation of PTEN gene).
Prognosis
1. Ganglioglioma: WHO grade 1, good prognosis with gross total resection. If subtotal resection, 41% progress. Rare malignant transformation from glial component.
2. Neurocytoma: WHO grade 1, good prognosis with resection. Recurrence, and CSF spread are rare.
3. DNTs: WHO grade 1, slow growing. Surgery may be needed for seizure management.
4. Lhermitte-Duclos disease: Good with resection.
Diagnosis
Location
1. Gangliogliomas have a predilection for temporal lobe but also occur in the basal ganglia, optic pathway, brainstem, pineal gland, cerebellum, and spinal cord.
2. Neurocytomas are intraventricular, usually in body of lateral ventricle, attached to septum pellucidum. Rarely in pons, cerebellum, spinal cord, or brain parenchyma.
3. DNTs involve predominantly the cerebral cortex, especially temporal lobes.
4. Lhermitte-Duclos disease occurs in cerebellum.
Clinical Presentation
1. Gangliogliomas usually present with seizures and, less often, headaches and focal deficits.
2. Neurocytomas present with symptoms of hydrocephalus.
3. DNTs usually have chronic complex partial seizures and a long-standing history of intractable focal epilepsy.
4. Lhermitte-Duclos disease presents with ataxia and hydrocephalus.
Diagnostic Tests
1. Ganglioglioma: MRI is nonspecific and shows a well-demarcated, superficial, nonenhancing mass with increased T2 and FLAIR signal. Can have cysts or calcification.
2. Neurocytoma: MRI shows a heterogenous ventricular mass with multiple cysts, calcification, occasional hemorrhage, variable enhancement; some have a “honeycomb” appearance on T1-weighted images.
3. DNT: MRI shows a T1 hypointense, T2 hyperintense mass with gyrus-like configurations, cortical dysplasia, variable enhancement.
4. Lhermitte-Duclos disease: MRI shows increased T2 and FLAIR abnormality in cerebellum with striped “tigroid” appearance.
Pathology
1. Gangliogliomas, WHO grade 1, have neuronal and astrocytic neoplastic cells, granular bodies, Rosenthal fibers, large irregular ganglion cells, and perivascular infiltrates. Associated with BRAF V600E mutations.
2. Neurocytomas, WHO grade 1, have small, uniform, well-differentiated neuronal cells, frequently misdiagnosed as oligodendrogliomas.
3. DNTs, WHO grade 1, have a glioneuronal element, nodular component, and cortical dysplasia. Associated with fibroblast growth factor receptor 1 (FGFR1) gene alterations and BRAF V600E mutations.
4. Gangliocytomas, WHO grade 1, are well-differentiated neoplastic cells with neuronal characteristics, no malignant transformation.
5. Lhermitte-Duclos disease is also known as dysplastic cerebellar gangliocytoma, WHO grade 1, and is characterized by loss of normal cerebellar cortical architecture and focal thickening of the folia. Associated with PTEN/Akt pathway abnormalities. Linked to PTEN germline mutations in familial cases.
Treatment
1. Surgical resection; complete resection is curative for all these conditions.
2. RT may have limited role for recurrent gangliogliomas, recurrent neurocytomas.
Pineal Parenchymal Tumor
Background
1. Rare tumors that account for less than 1% of all intracranial tumors; 14% to 30% of pineal region tumors.
2. Histologies include pineocytomas, pineoblastomas, pineal parenchymal tumor of intermediate differentiation (PPTID), papillary tumor of the pineal region (PTPR), and SMARCB1-mutant desmoplastic myxoid tumor of the pineal region.
3. Pineocytoma most common between 25 and 35 years; pineoblastoma most common in the first two decades.
Pathophysiology
1. Pineocytoma, pineoblastoma, and PPTIDs arise from parenchymal epithelial cells (pinealocytes) in the pineal gland.
2. PTPRs believed to arise from specialized secretory ependymocytes of the subcommissural organ.
Prognosis
1. Pineocytoma is slow growing and has favorable prognosis following resection; 86% 5-year survival.
2. Pineoblastoma has poorer prognosis; less than 50% 5-year survival. Associated with leptomeningeal dissemination.
3. PPTIDs and PTPRs have an intermediate prognosis.
4. Prognosis of SMARCB1-mutant desmoplastic myxoid tumor of the pineal region is unclear due to its rarity.
Diagnosis
Location
1. Pineal region.
a. Pineocytoma, pineoblastoma, PPTIDs, and SMARCB1-mutant desmoplastic myxoid tumor of the pineal region arise from pineal gland.
b. PTPRs arise from the subcommissural organ located in the posterior third of the third ventricle.
2. Pineoblastoma can disseminate to the leptomeninges.
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