Brain tumors

Brain tumors are masses of abnormal cells within the brain. They can be primary or metastatic, benign or malignant. Common tumors in children are pilocytic astrocytomas, medulloblastomas, ependymomas, and craniopharyngiomas. Adults most often develop glioblastoma multiforme, meningiomas, hemangioblastomas, schwannomas, oligodendrogliomas, and pituitary adenomas. Clinical features and radiological findings vary according to the type, location, and onset of the tumor. Magnetic resonance imaging (MRI) is the primary diagnostic method. Removal of the entire tumor is a prerequisite for remission. The histological grade of the tumor, which is determined postoperatively, is an important factor in determining the prognosis. Malignant tumors usually require additional treatment with radiotherapy and/or chemotherapy.

Meningiomas, pituitary adenomas, and schwannomas are discussed in separate articles.

Overview

Primary brain tumors arise within the CNS and are classified based on the growth characteristics and cell type from which the tumor arises.

By the spreading potential

By the cell type

• Gliomas (e.g., astrocytomas and oligodendrogliomas)
• Choroid plexus tumors (e.g., choroid plexus papilloma, choroid plexus carcinoma)
• Neuronal and mixed neuronal-glial tumors (e.g., paraganglioma, central neurocytoma)
• Meningiomas (see “Classification of meningiomas”)
• Embryonal neuroectodermal tumors (e.g., medulloblastoma: , CNS neuroblastoma)
• Pituitary tumors: a group of tumors that arise from the pituitary gland (e.g., pituitary adenoma, craniopharyngioma)
• Pineal tumors
• Tumors of the cranial and paraspinal nerves (e.g., schwannoma: , neuroma, neurofibroma)
• Mesenchymal nonmeningeothelial tumors (e.g., hemangiomas, hemangioblastoma, lipoma, hamartoma)
• Germ cell tumors (e.g., teratoma)
• Primary central nervous system lymphoma (PCNSL)

Epidemiology

• Approx. 30% of brain tumors are primary brain tumors, while approx. 70% are metastases.
• Approx. 40% of primary brain tumors are benign.
• Sex: ♂ > ♀ (except meningiomas, which occur more frequently in women) ^[1]

Clinical features

Symptoms depend on the type and location of the tumor (see “Primary brain tumors according to age” below). Onset is usually insidious.

• Headaches (present from the onset in ∼ ⅓ of cases)
• Seizures
• Focal neurologic deficits based on the location of the tumor
  • Motoric deficits
  • Aphasia
  • Sensory deficits (e.g., visual field defects)
• Cognitive, behavioral, and personality changes
• Symptoms of elevated intracranial pressure and brain herniation (e.g., papilledema, decreased level of consciousness)

Metastasis

• Primary CNS tumors do not metastasize to organs outside the CNS.
• Drop metastases (intradural extramedullary spinal metastases ) and leptomeningeal metastases may occur. ^[2]
  • Typically manifest as nodules along the spine and cauda equina that can cause back pain with neurologic symptoms (e.g., limb weakness)
  • Can be detected by lumbar puncture

Overview

Astrocytomas are neuroepithelial tumors (gliomas) that arise from astrocytes, which are a specific type of glial cell.

Pilocytic astrocytoma ^{[8][9][10][11]}

• Description: slow-growing, circumscribed, non-invasive tumor
• Epidemiology
  • Most commonly affects children and young adults (< 20 years)
  • The most common primary brain tumor of childhood
• Associated conditions: neurofibromatosis type I
• Typical location
  • Cerebellum (most common)
  • Cerebral hemispheres (supratentorial)
• Clinical features
  • Insidious onset and slow progression of symptoms
  • Vomiting
  • Ataxia
  • Failure to thrive
• Diagnostics
  • MRI findings
    • Well-demarcated cystic lesion
    • Bright contrast-enhancing solid nodule in the wall of the cyst
  • Histopathology
    • Microcysts
    • Bipolar cells; hair-like projections
    • Eosinophilic fibers with corkscrew appearance (Rosenthal fibers)
• Treatment: Surgical resection
• Prognosis
  • Favorable prognosis: high rates of long-term survival
  • Curable with complete resection of the tumor
  • Median survival: > 10 years

Optic glioma ^[12]

• Description
  • Low-grade, slow-growing tumor that arises from the glial cells of the optic pathway
  • Typically a grade I pilocytic astrocytoma
• Epidemiology: most frequently in children (< 10 years)
• Associated conditions: neurofibromatosis type I
• Clinical features
  • Insidious onset and slow progression of symptoms
  • Proptosis
  • Strabismus
  • Asymmetric nystagmus
  • Impaired vision (in case of chiasmal involvement)
• Diagnostics
  • Fundoscopy findings: retinal pallor, papilledema
  • MRI findings: thickening of the optic nerve or optic chiasm; suprasellar mass
• Treatment
  • No treatment in asymptomatic patients with no signs of tumor growth
  • Surgical resection
  • Radiotherapy
    • Unresectable tumors, e.g., chiasmal or optic tract lesions in optic glioma
    • Adjuvant to surgery
• Prognosis
  • Favorable; high rates of long-term survival
  • Many patients have long-term visual impairment.

Diffuse astrocytoma

• Description: slow growing, infiltrative tumor that arises from glial cells in the CNS and has the potential to progress to higher-grade tumors
• Epidemiology: peak age 20–40 years
• Location: cerebral hemispheres
• Clinical features
  • Insidious onset and slow progression of symptoms
  • Initially manifest with nonspecific features such as headaches, seizures
  • Focal symptoms may develop (e..g, progressive paralysis, aphasia)
• Diagnostics
  • CT: hypodense lesion with no contrast enhancement
  • MRI
    • T1 hypointense or isointense
    • T2 hyperintense
• Treatment
  • Complete surgical resection often not possible resection until definable margins can be attempted
  • Percutaneous radiotherapy for very diffuse, unresectable tumors
• Prognosis: incurable; median survival: 2–12 years

Anaplastic astrocytoma ^[3][4]

• Description: A high-grade infiltrative tumor with variable rates of growth that arises from glial cells in the CNS
• Epidemiology: peak age 30–50 years of age
• Clinical features
  • Headache
  • Seizures
  • Focal neurologic deficits
  • Altered mental status
• Diagnostics
  • MRI
    • Inhomogenous lesion with perifocal edema
    • No necrosis (in contrast to glioblastoma)
  • CT
    • Hypodense lesion with variable contrast enhancement
    • Positive mass effect
• Treatment
  • Tumor debulking through surgery However, complete surgical resection is not possible.
  • Percutaneous radiotherapy/chemotherapy
• Prognosis: incurable; median survival between 18 months and 10 years

Glioblastoma multiforme

• Description: : a highly malignant tumor derived from glial cells (e.g., astrocytes)
• Epidemiology ^[13][14][15]
  • Most common malignant brain tumor
  • Accounts for approx. 16% of all CNS neoplasms
  • ♂ > ♀ (1.6:1)
  • Peak incidence: 64 years of age
    • Primary glioblastoma (∼ 90%): more frequent in elderly patients (6^th decade of life)
    • Secondary glioblastoma (∼ 10%): affects primarily younger patients (4^th decade of life)
• Etiology
  • Environmental factors: ionizing radiation
  • Genetic or chromosomal factors ^[14]
    • Primary glioblastoma: arises de novo
      • EGFR overexpression
      • PTEN gene mutations ^[16]
      • Loss of chromosome 10q
    • Secondary glioblastoma: arises from a preexisting low-grade tumor (e.g., diffuse astrocytoma, anaplastic astrocytoma)
      • Isocitrate dehydrogenase 1 (IDH1) mutations
      • p53 gene mutations
      • Loss of chromosome 19q
• Associated conditions: rare occurrence of glioblastoma in patients with certain genetic syndromes (e.g., type I and II neurofibromatosis, tuberous sclerosis, Li Fraumeni syndrome, Turcot syndrome)
• Classification: The 2016 WHO classification groups glioblastomas mainly on the basis of IDH mutation status. ^[17]
  • IDH-wildtype glioblastoma (∼ 90%): usually corresponds with the clinically defined primary glioblastoma
  • IDH-mutant glioblastoma (∼ 10%): usually corresponds with the clinically defined secondary glioblastoma
• Clinical features
  • General clinical features of brain tumors (e.g., signs of ↑ ICP, seizures, focal neurologic symptoms)
  • Short disease course with death within weeks (Rapid tumor growth)
  • Apoplectic glioma: mimics intracranial hemorrhage and manifests with signs of ↑ ICP
• Typical location
  • Primary glioblastoma
    • White matter of the cerebral hemispheres (supratentorial)
    • Possibly bilateral, crossing the corpus callosum: butterfly glioma
  • Secondary glioblastoma: frontal lobe
• Diagnostics
  • Characteristic features on MRI and CT
    • Irregularly shaped, inhomogeneous mass
    • Perifocal vasogenic edema
    • Mass effect: midline shift, ventricular distortion
    • Possibly hemorrhage
  • MRI (gadolinium-enhanced)
    • Garland-like, enhanced margins with a hypointense necrotic core
    • T1 hypointense
    • T2 hyperintense
    • May also have multifocal enhancements
  • Contrast-enhanced CT: irregular, heterogeneous enhancement of the margins and hypointense center
  • Evaluation of IDH mutation status (via immunohistochemistry or genome sequencing)
  • Biopsy
    • Dense, pleomorphic anaplastic cells that form pseudopalisades due to central necrosis or hemorrhage
      • A histopathologic finding characterized by elongated nuclei stacked in rows that often radiate away from a central area of necrosis
      • Classically associated with glioblastoma multiforme
    • Microvascular proliferation
    • GFAP positive
• Treatment
  • Surgical resection
  • Palliative radiochemotherapy with temozolomide
  • Adjuvant chemotherapy with temozolomide
  • Glucocorticoids
  • After recurrence
    • Reresection, temozolomide, and/or radiation (if tolerated)
    • The use of other chemotherapeutic agents (carboplatin, etoposide, irinotecan, nitrosoureas) can be tried as single agents or in regimens.
    • Bevacizumab
    • Tumor-treating fields (TTFields) ^[18]
      • Noninvasive treatment modality based on the transcutaneous delivery of alternating intermediate-frequency and low-intensity electric fields to disrupt tumor cell division and inhibit tumor growth
      • The electric field interferes with cancer cells in a number of ways, including the alteration of cell membrane polarization and inhibition of microtubule polymerization.
      • Can be given in combination with adjuvant chemotherapy (e.g., temozolomide)
• Prognosis ^[14]
  • Median survival: 15 months
  • Positive prognostic factors: IDH-mutant glioblastoma, lower patient age, higher Karnofsky performance score, accessible tumor location for surgery
  • Negative prognostic factors: large tumor size (> 5–6 cm), midline-crossing tumors

Glial fibrillary acidic protein (GFAP) is an important diagnostic marker for astrocytomas; it is almost always positive in glioblastoma multiforme!

Brainstem glioma ^[19]

• Description: a tumor arising from the glial cells in the brainstem that may be low-grade (I-II) or high-grade (III-IV)
• Epidemiology: peak age 3–10 years
• Clinical features
  • Vomiting
  • Cranial nerve deficits
  • Ataxia
  • Hydrocephalus
  • Upper motor neuron signs
• Diagnostics: MRI
  • No contrast enhancement
  • T2 hyperintense lesion
• Treatment
  • Radiation and/or chemotherapy
  • Surgical resection is often impossible
• Prognosis
  • Poor, especially in diffuse pontine gliomas
  • Median survival: ∼ 10 months

• Description: : a tumor that arises from oligodendrocytes
• Epidemiology
  • Median age: 40–50 years
  • Relatively rare: ∼ 10% of primary CNS tumors
• Clinical features: : the most common location is the cerebral hemisphere (typically the frontal lobe) → seizures, focal neurological deficits, personality changes
• Diagnostics
  • Imaging: intra-parenchymal tumor with calcifications ^[20]
    • CT: hypodense lesion
    • MRI
      • T1: hypointense or mixed lesions
      • T2: hyperintense lesions
  • Biopsy ^[21]
    • Cells with a clear cytoplasm and round nucleus (fried egg cells)
    • Chicken-wire pattern of capillary anastomoses
  • Molecular testing: assessment of 1p/19q codeletion ^[22]
• Treatment
  • Resection
  • Adjuvant radiotherapy and chemotherapy
• Prognosis
  • Recurrence rate ∼ 100%
  • 5-year survival rate 50–60%

• Description: a tumor that arises from ependymal cells of the ventricular system
• Epidemiology: peak incidence in children and young adults
• Associated conditions: neurofibromatosis type II
• Clinical features: the 4^th ventricle is the most common location in children → noncommunicating hydrocephalus → features of increased intracranial pressure (e.g., papilledema, headache)
• Diagnostics
  • Imaging: intra-parenchymal tumor with calcifications and cystic components due to necrosis and/or hemorrhage
  • Biopsy
    • Perivascular pseudorosettes
    • Rod-shaped bodies (blepharoplasts) near the nucleus
• Treatment
  • Resection
  • Adjuvant radiotherapy
• Prognosis
  • Depends on the WHO grade, but usually poor
  • Overall 5-year survival rate: 65–90% ^[23][24]

• Description: a highly malignant tumor derived from primitive, neuroectodermal tissue ^[25]
• Epidemiology
  • Peak incidence: 1^st decade
  • Most common malignant pediatric brain tumor (20–25% of all cases)
• Associated conditions: Turcot syndrome
• Clinical features ^[26]
  • The most common location is the cerebellum → cerebellar defects (e.g., broad-based gait)
  • Most tumors arise within the cerebellar vermis (midline) → truncal ataxia
  • Invasion or compression of the 4^th ventricle → noncommunicating hydrocephalus → features of raised intracranial pressure (e.g., papilledema, vomiting, headache)
  • Drop metastases to the spinal cord are common → paraplegia
• Diagnostics ^[27]
  • Imaging: intraparenchymal contrast-enhancing mass ^[28]
    • CT scan: isodense or hyperdense mass
    • MRI
      • T1: hypointense mass
      • T2: isointense mass
  • Biopsy: anaplastic small round blue cells; that surround a central neuropil (Homer-Wright rosettes) ^[29]
• Treatment
  • Resection
  • Adjuvant therapy
    • Children ≥ 3 years: chemotherapy and craniospinal radiotherapy
    • Children < 3 years: chemotherapy
• Prognosis
  • 5-year survival rate: 60–80% ^[30][31]
  • Poor prognostic factors ^[32]
    • Inadequate resection
    • Presence of drop metastases
    • HER2/neu mutation

• Description: a relatively benign dysontogenetic tumor arising from a remnant of the Rathke pouch (ectodermal derivative)
• Epidemiology
  • Bimodal distribution: 5–14 years; second peak at 50–75 years
  • Most common childhood supratentorial tumor
• Clinical features: The tumor arises in the suprasellar region and can extend into the intrasellar region. ^[33]
  • Compression of the pituitary gland due to intrasellar extension → hypopituitarism
    • Hypogonadotropic hypogonadism
    • Failure to thrive
    • Central diabetes insipidus
  • Compression of the ventromedial hypothalamic nucleus → hyperphagia and obesity
  • Compression of the infundibular stalk → disconnection hyperprolactinemia
  • Compression of the optic chiasm → bitemporal hemianopsia
  • Compression of interventricular foramina and/or aqueduct → obstructive hydrocephalus
• Diagnostics ^[34]
  • Imaging: suprasellar calcified cyst with a lobulated contour
  • Biopsy: cholesterol crystals found in a motor oil-like fluid on gross examination
• Histological variants
  • Adamantinomatous (common)
    • Reticular epithelial cells
    • Frequently associated with calcifications
    • Cysts and keratin nodules
  • Papillary
    • Metaplastic squamous cells
    • Calcifications and cysts are rare.
    • No keratin nodules
• Differential diagnoses
  • Pituitary adenoma
  • Rathke cleft cyst
• Treatment
  • Resection
  • Adjuvant radiotherapy
  • In the case of hypopituitarism: hormone replacement therapy
• Prognosis: generally good, with a 10-year survival rate of ∼ 90%; however, the recurrence rate is high ^[35][36][37]

• Description: a tumor that forms in or near the pineal gland and includes pineocytomas, pineoblastomas, and pineal germinomas
• Epidemiology
  • ♂ > ♀
  • < 1% of all CNS tumors in adults
• Clinical features
  • Compression of dorsal midbrain leads to:
    • Compression of tectum → vertical gaze palsy (Parinaud syndrome)
    • Compression of cerebral aqueduct → noncommunicating hydrocephalus
    • Compression of hypothalamic inhibiting pathways → increased hCG secretion → precocious puberty
• Histology
  • Approx. 70% are germinomas (appear similar as testicular seminoma)
  • Large vacuolated cells with round nuclei (fried egg cells)
  • Lymphoid stroma
• Treatment
  • Resection
  • Adjuvant radiochemotherapy

• Description: : a benign, highly vascularized neoplasm
• Epidemiology
  • Rare
  • Peak incidence: 20–50 years
• Associated conditions: von Hippel-Lindau disease
• Clinical features
  • The cerebellum is the most common location → cerebellar defects
  • Compression of the 4^th ventricle → non-communicating hydrocephalus → features of raised ICP (e.g., papilledema, headache)
  • Erythropoietin production by tumor cells → secondary polycythemia
• Diagnostics
  • MRI; : sharply demarcated intra-parenchymal cystic mass with a non-enhancing wall and an enhancing mural nodule in ∼ 60% of cases ^[38][39]
    • T2: hyperintense mass
    • T1: hypointense or isointense mass
  • Biopsy: thin-walled capillary vessels, densely packed together with scarce parenchyma
• Treatment
  • Resection
  • Antiangiogenic therapy
• Prognosis: Recurrence risk is < 20% in sporadic cases. ^[40]

Pediatric primary brain tumors ^[41]

• Most pediatric brain tumors are primary.
  • Most common type of benign pediatric primary brain tumor: pilocytic astrocytoma
  • Most common malignant pediatric primary brain tumor: medulloblastoma
• Brain tumors are the second most common cause of pediatric cancer; after leukemia, accounting for approx. 20% of all cases of pediatric cancer and the primary cause of pediatric cancer deaths in the US.

In children, most primary brain tumors arise infratentorial, craniopharyngiomas being an important exception.

Adult primary brain tumors ^[41]

• Primary brain tumors are less common than brain metastases in adults.
  • Most common benign primary brain tumor in adults: meningioma
  • Most common malignant primary brain tumor in adults: glioblastoma multiforme
• Primary brain tumors account for approx. 2% of cancer cases in adults.

In adults, most primary brain tumors arise supratentorially, hemangioblastomas and schwannomas being important exceptions.

• Epidemiology: : most common cause of brain tumors in adults
• Etiology
  • Lung cancer (most common)
  • Breast cancer
  • Malignant melanoma
  • Renal cell carcinoma
  • Colorectal carcinoma
  • Pancreatic cancer
  • Testicular cancer
• Clinical features: acute or subacute onset of symptoms due to rapid tumor growth
  • Seizures
  • Focal neurological deficits
  • Cognitive deficits
  • Headaches
• Diagnostics
  • Imaging: well-circumscribed tumors at the junction of gray and white matter and/or watershed areas of the arterial system ^[45]
    • Large metastases: ring enhancement due to central necrosis
    • Small metastases: homogeneous enhancement
  • If the primary tumor is unknown: whole-body contrast CT and/or PET scan
  • If no primary tumor is found or if the tumor is not surgically accessible: biopsy of the brain metastasis
• Treatment ^[46]
  • Primary therapy
    • Limited brain metastases: surgical resection or stereotactic radiosurgery (e.g., Gamma Knife, CyberKnife, proton beam)
    • Extensive brain metastases: stereotactic radiosurgery, whole-brain radiation therapy, or chemotherapy
  • Glucocorticoids to reduce tumor edema
  • Patients with a high primary tumor burden and a poor functional status (Karnofsky score) can be treated palliatively.
• Prognosis ^[47]
  • Without treatment: mean survival ∼ 1 month
  • With treatment: mean survival < 1 year

• Consult neurosurgery and oncology.
• Start VTE prophylaxis. ^[48]
• Manage increased intracranial pressure (ICP), if present.
  • Urgent neurosurgery and anesthesiology consult
  • Assess and secure the airway.
  • Consider therapeutic hyperventilation.
  • Consider dexamethasone in patients with cerebral edema.
  • Consider mannitol
  • Admission to ICU and ICP monitoring
• Serial neurologic examination
• Admission to neurology or oncology service