CNS Tumors

Question 1

CNS Tumors

Epidemiology

Answer 1

• Adults
  
  • 1° CNS tumors uncommon in adults
  • Represent 1.2% of all autopsy deaths and 9.2% of all primary neoplasms
  • Gliomas are the most common
• Children
  
  • Tumors of the CNS account for nearly 20% of all cancers of childhood

Question 2

CNS Tumors

Clinical Features

Answer 2

• Clinical course is strongly influenced by patterns of growth and location
• Low grade + diffuse infiltration ⇒ serious clinical deficits and poor prognosis
• Location & infiltrative growth ⇒ may not be amenable to complete surgical resection w/o compromising neurologic function
• Any CNS neoplasm may have lethal consequences if situated in a critical region of the brain

Question 3

CNS Tumor

Origin

Answer 3

No longer thought that these tumors derive from their specific, mature cell types (astrocytes, oligodendrocytes, and ependymal)

Arise from a progenitor cell that preferentially differentiates down one of the cellular lineages

Question 4

Primary CNS Tumor

Growth Pattern

Answer 4

Primary tumors in the CNS are typically diffusely infiltrative

• Spread along nerve fascicles and in the subpial and subependymal regions
• Extra neural spread of tumors is rare and usually seen only after multiple surgical interventions
• Metastases of CNS tumors are not common
• More malignant ones, especially medulloblastoma may spread along the pathways of cerebrospinal fluid flow

Question 5

Metastatic CNS Tumor

Growth Pattern

Answer 5

• Often reaches CNS as a tumor embolus ⇒ lodges at the grey-white junction
• They are rarely infiltrative, and instead push brain tissue away from growing borders
• Because of the mechanism of tumor embolization, tumor spread often is microscopically perivascular

Question 6

Supratentorial Tumors

Answer 6

• Tumors occur above the tentorium ⇒ in the hemispheres
• Comprise 2/3 of the tumors in adults
• Comprises 1/3 of the tumors in children
• Of these supratentorial tumors: gliomas > meningiomas > metastases

Question 7

Infratentorial Tumors

Answer 7

• Tumors occurring in the posterior fossa ⇒ in the cerebellum and brain stem
• Comprise 1/3 of the tumors in adults
• Comprises 2/3 of the tumors in children

Question 8

Cerebral Edema & Herniation

Answer 8

Question 9

Spinal Tumor

Classification

Answer 9

• Extradural
  
  • Form outside the dura, usually in the vertebral body
  • The most common extradural tumors in adults are metastases, followed by primary tumors of bone
• Intradural
  
  • Tumors within the intradural compartment includes:
  • Subdural space between the dura and the spinal cord
  • Spinal cord itself (intramedullary tumors)

Question 10

Spinal Tumor

Types

Answer 10

• Meningiomas are the most frequent type ⇒ subdural
  
  • Usually attached to the inner surface of the dura
• Ependymomas ⇒ intramedullary
• Astrocytomas ⇒ intramedullary

Question 11

Classification of Brain Tumors

Answer 11

In 2016 the WHO completely revised the classification:

• Previously based on histologic type ⇒ 2007 classification
• Now utilizes both histologic and molecular data ⇒ 2016 classification
  
  • Groups have changed dramatically
  • In discordant cases, genotype trumps histologic phenotype
  • ‘Not Otherwise Specified’ (NOS) category used for cases where genetic analysis is not possible or inconclusive
    
    • It does NOT serve as a default category

Question 12

Grading of Brain Tumors

Answer 12

WHO grade determination is made based upon histology

Question 13

CNS Tumor

Diagnosis & Naming

Answer 13

• Histopathological name followed by the genetic features
• Example: Diffuse astrocytoma, IDH-mutant
• If more than one genetic determinant, all included
  
  • Example: Oligodendroglioma, IDH-mutant and 1p/19q codeleted
• For tumors lacking genetic mutation, the term wildtype can be used if an official wildtype exists
  
  • Example: Glioblastoma, IDH-wildtype
• For a tumor lacking a diagnostic mutation or where analysis cannot be performed, a NOS designation is given
  
  • Example: Diffuse astrocytoma, NOS

Question 14

Gliomas

Overview

Answer 14

• Most common group of primary brain tumors
• Arises from a progenitor cell that preferentially differentiates along one of the cellular lineages
  
  • Previously classified based on their morphologic resemblance to different types of glial cells
• Molecularly distinct family of neoplastic lesions, independent of their histologic patterns
  
  • Currently dx based upon combined histologic patterns and molecular characterization
• Majority in adults are diffuse astrocytomas and oligodendrogliomas

Question 15

Gliomas

Genetic Alterations

Answer 15

• IDH1 or IDH2 Mutations
  
  • Isocitrate dehydrogenase (IDH1 – cytosolic, IDH2 – mitochrondrial)
  • Gain of function mutation
    
    • Mutated cells: α-ketoglutarate → “oncometabolite” 2-hydroxyglutarate ⇒ metabolic reprogramming of the cell
    • Remain in a stem cell-like state ⇒ more prone to self-renewal and tumorigenesis
  • Most common IDH1 mutation at codon 132 (85-90% cases) ⇒ can be detected w/ immunohistochemical stain
  • IDH2 mutations ⇒ require sequencing or other technique for detection
  • IDH mutation analysis REQUIRED for classification of Diffuse Glioma
  • Mutation is a specific tumor marker ⇒ is NOT seen in reactive conditions
    
    • Present in 85-90% of low-grade gliomas in adults
    • Mutation almost never found in children (< 14 years)
  • Grade for grade, IHD mutated tumors have a better prognosis than IDH wild type tumors
• ATRX Mutations
  
  • Loss of function mutation
  • ATRX normally suppresses recombination events that can preserve telomere length ⇒ “alternative lengthening of telomeres”
  • Immunohistochemical stain specific for normal protein ⇒ ⊖ in mutated cells
• 1p 19q Deletions
  
  • Co-deletion of 1p and 19q required for dx of oligodendroglioma
  • FISH analysis for dx
  • Mechanism for ∆ tumor morphology and response to tx unknown

Question 16

Astrocytoma

Overview

Answer 16

• Infiltrating astrocytomas account for ~ 80% of adult primary brain tumors (4th– 6th decade)
• Usually in the cerebral hemispheres
• Also in cerebellum, brainstem, or spinal cord
• Clinical: Present w/ seizures, headaches and focal neurologic deficits
• Spectrum of histologic differentiation that correlates well w/ clinical course and outcome

Question 17

Astrocytoma

Subtypes

Answer 17

Histologically stratified into three groups w/ increasingly poor prognosis:

Diffuse astrocytoma (grade II)

Anaplastic astrocytoma (grade III)

Glioblastoma (grade IV)

Question 18

Diffuse Astrocytoma

Answer 18

“Infiltrating Astrocytoma”

• Poorly delineated hemispheric mass
• ↑ Density of astrocytes w/o histologic features of high grade astrocytomas
• May be low or high grade at presentation
  
  • Survival in low grade up to 20 years after primary dx
• Most will evolve into a high grade, aggressive tumor ⇒ Secondary GBM
• IDH analysis required for dx of diffuse astrocytoma in adults
  
  • IDH status more prognostically important than grade
• Pediatric astrocytomas have different genetic abnormalities than adult tumors
  
  • IDH mutation almost never found in children (<14 years)

Question 19

Anaplastic Astrocytomas

Answer 19

• High grade astrocytoma
• Densely cellular w/ greater nuclear pleomorphism
• Mitotic figures are often observed

Question 20

Glioblastoma (GBM)

Answer 20

• High grade astrocytoma
• Variation is characteristic w/ some areas firm and others are soft due to necrosis +/- cystic degeneration and hemorrhage
• Microscopic is similar to anaplastic astrocytoma plus necrosis and/or vascular/endothelial cell proliferation
• Necrosis in glioblastoma shows a pseudo-palisaded appearance
• 10% survival at two years

Question 21

Glioblastoma (GBM)

Types

Answer 21

• Primary GBM
  
  • Majority of cases
  • Arise de novo in older patients
  • Typically IDH-wildtype
  • Poor prognosis
• Secondary GBM
  
  • Minority of cases
  • Younger patients
  • Arise from a lower grade precursor lesion
  • IDH mutations common
  • Better prognosis

Question 22

Localized Astrocytomas

Answer 22

Question 23

Pilocytic Astrocytoma

Answer 23

• Most common localized astrocytoma
• Tumors of children and young adults
• Locations: cerebellum >> third ventricle, optic pathways, spinal cord >> cerebral hemispheres
• Relatively benign behavior
• Limited infiltration
• Bipolar cells w/ long, thin “hairlike” processes that form dense fibrillary meshwork
• Rosenthal fibers and eosinophilic granular bodies are characteristic findings
• Necrosis and mitosis uncommon
• Commonly have activating mutations or translocations of BRAF ⇒ ⊕ MAPK signaling pathway
  
  • May be treated w/ BRAF inhibitors, esp when location prevents removal
• Do not have mutations in IDH1 and IDH2

Question 24

Oligodendroglioma

Answer 24

Infiltrating glioma comprised of cells that resemble oligodendrocytes

• 5-15% of gliomas
• 4thto 5th decades
• Clinical: often several years of neurologic complaints, often including seizures
• Cerebral hemispheres ⇒ white matter
• Well circumscribed, gelatinous w/ cysts, focal hemorrhage, and calcification
• Microscopically: sheets of cells resembling normal oligodendrocytes w/ clear, vacuolated cytoplasm and a delicate network of anastomosing capillaries
• Calcification (90% of tumors) ⇒ ranges from microscopic foci to massive depositions
• Mitotic activity is minimal or absent
• WHO grade II lesions
• IDH mutation and 1p/19q codeletion REQUIRED for diagnosis
• Pediatric tumors often do NOT demonstrate IDH mutation and 1p19q codeletion ⇒ these tumors currently classified NOS category

Question 25

Ependymoma

Answer 25

• Often arise next to the ependyma-lined ventricular system
  
  • Tumors of fourth ventricle during first two decades of life
  • Tumor of spinal cord in middle life
    
    • Neurofibromatosis type 2 (NF2) pts commonly have spinal cord lesion
    • Tumors show abnormalities in the NF gene on chromosome 22 are common
• Grading difficult and of questionable clinical utility
• Gross: usually solid and sharply demarcated from surrounding tissue
• Micro: ependymal canals – rosettes - tumor

Question 26

Ependymoma

RELA Fusion Positive

Answer 26

Variant accounts for majority of supratentorial tumors in children

Poor prognosis

Question 27

Medulloblastoma

Answer 27

• Malignant embryonal tumor
• Predominantly children
• Exclusively in the cerebellum
  
  • Histologically similar lesion may arise in the hemispheres ⇒ was termed CNS PNET, now embryonal tumors
• Largely undifferentiated and corresponds to WHO grade IV
• Often well-circumscribed, gray, and friable
• Rapid growth may occlude the flow of CSF ⇒ hydrocephalus
• Microscopic very densely cellular w/ sheets of anaplastic cells and rosettes
• Mitoses are abundant
• Frequently disseminates along the CSF flow ⇒ ependymal and subarachnoid tumor implants
• ∆ in signaling pathways involved in normal cerebellar development ⇒ basis for classification
• Treatment: aggressive surgical removal followed by radiation of brain and spinal cord +/- chemo

Question 28

Medulloblastoma

Subtypes

Answer 28

Four genetically defined groups:

• Medulloblastoma, WNT-activated
• Medulloblastoma, SHH activated
• Group 3 Medulloblastoma
• Group 4 Medulloblastoma

Question 29

Medulloblastoma, WNT-activated

Answer 29

• GOF mutations in β-catenin
• Most favorable prognosis
• Older children
• Histology: classic-type tumors
• Monosomy of chromosome 6 and nuclear expression of β-catenin

Question 30

Medulloblastoma, SHH activated

Answer 30

• LOF mutations in PTCH1 ⇒ negative regulator of Hedgehog
• SHH activated & TP53 wildtype ⇒ intermediate prognosis
• SHH activated & TP53 mutant ⇒ very poor prognosis
• Infants or young adults
• Nodular desmoplastic histology
• ± MYC amplification
• Medulloblastoma, non-WNT/non-SHH

Question 31

Group 3 Medulloblastoma

Answer 31

Medulloblastoma, non-WNT/non-SHH

• Often MYC amplification
• Isochromosome 17 (i17q) ⇒ poor prognosis
• Infants and Children
• Classic or large cell histology
• Worst Prognosis

Question 32

Group 4 Medulloblastoma

Answer 32

Medulloblastoma, non-WNT/non-SHH

• Isochromosome 17 (i17q) ⇒ poor prognosis
• Classic or large cell histology
• No MYC amplification
• Intermediate prognosis

Question 33

Meningioma

Answer 33

• Predominantly benign tumors of adults
• Arise from meningothelial cells of the arachnoid
• Attached to the dura
  
  • Found along external surfaces of brain and within ventricular system
• Prior radiation therapy to the head and neck is a risk factor
• Female to male = 3:2
• Rounded masses w/ well-defined dural bases that compress underlying brain but are easily separated from it
• Microscopically show whorls and calcifications (psammoma bodies)
• Low risk of recurrence or aggressive growth ⇒ WHO grade I/IV
• Usually diagnosed by CT or other scans
• Does not invade the brain
• Most common cytogenetic abnormality is loss of 22q
  
  • Seen in 50-60% of sporadic meningiomas

Question 34

CNS Lymphomas

Answer 34

• Can be primary in CNS or metastatic
• Diffusely infiltrates the brain
• Microscopically perivascular collections of lymphocytes

Question 35

Primary CNS Lymphoma

Answer 35

• 2% of extranodal lymphomas and 1% of intracranial tumors
• Most common CNS neoplasm in immunosuppressed individuals (AIDS & transplant patients)
  
  • Immunosuppressed patients ⇒ associated w/ Epstein-Barr virus
  • Transplant patients ⇒ associated w/ a systemic post-transplantation lymphoproliferative disorder
• Often multifocal within the brain parenchyma
• Involvement outside of the CNS in lymph nodes or bone marrow is a rare and late complication
• Majority are B-cell origin
• Aggressive and have worse outcomes vs comparable tumors in non-CNS sites

Question 36

Metastatic Lymphoma

Answer 36

• Lymphoma arising outside the CNS rarely involves the brain parenchyma
• Usually in the setting of significant disease burden outside of the CNS
• Dx by malignant cells within the CSF and around intradural nerve roots, and occasionally by the infiltration of superficial areas of the cerebrum or spinal cord

Question 37

CNS Metastasis

Answer 37

• Represents 25-50% of all brain tumors
• More common in older age group
• Most common primary sites: lung, breast, skin (melanoma), kidney, and GI tract ⇒ ~ 80% of all metastases
• Usually multiple lesions ⇒ well-circumscribed mass at the junction of the white and grey matter surrounded by significant edema
• Microscopically – looks like the primary tumor
• Treatment of solitary brain metastases improves the quality of the patient’s remaining life

Question 38

Spinal Cord Metastases

Answer 38

• Invade the epidural space from a primary metastatic site in the adjacent bone
• Main danger is spinal vertebral collapse
• Need to treat emergently to prevent paralysis

Question 39

Carcinomatous Meningitis

Answer 39

• Different presentation of metastatic tumor
• Tumor deposits throughout CNS in the subarachnoid space ⇒ widespread neurological dysfunction
• Can present as pain, cranial and peripheral nerve palsies or diffuse brain dysfunction
• Seen most often w/ adenocarcinomas, including carcinomas of the breast or stomach
• Can treat w/ radiation and chemotherapy

Question 40

Traumatic Neuroma

Answer 40

• Peripheral nerve tumor
• Non-neoplastic proliferation associated w/ previous injury of a peripheral nerve
  
  • If regenerating axons do not line up w/ transected end of the nerve ⇒ traumatic neuroma
• Clinically: presents w/ painful localized nodule following an injury
• Microscopically consists of a haphazard mixture of axons, Schwann cells, and connective tissue

Question 41

Schwannoma

Answer 41

• Peripheral Nerve Tumors
• Encapsulated nerve sheath tumor consisting microscopically of two components:
  
  • Highly ordered cellular component (Antoni A area) (Verocay bodies)
  • Loose myxoid component (Antoni B area)
• Encapsulation, two types of Antoni areas, uniformly intense immunostaining for S-100 protein distinguish schwannoma from neurofibroma
• Typically benign
• Adults in 5th and 6th decades
• 90% sporadic, 3% in patients w/ NF2, rare in NF1
• Solitary, circumscribed lesion
• Compresses but does not invade nerve
• Mostly seen in proximal nerves or spinal roots
• Potential for surgical removal

Question 42

Neurofibroma

Answer 42

Benign nerve sheath tumor of the PNS

2nd to 3rd decade

Question 43

Localized Neurofibroma

Answer 43

Superficial, solitary tumor in normal individuals

Question 44

Diffuse Neurofibroma

Answer 44

• Close association w/ neurofibromatosis 1 (NF1)
• Infiltrative proliferations that can take the form of large, disfiguring subcutaneous masses

Question 45

Plexiform Neurofibroma

Answer 45

• Virtually pathognomonic of neurofibromatosis 1 (NF1)
• Grow diffusely within the confines of a nerve or nerve plexus
• Grossly: fusiform, non-circumscribed enlargements of nerve, solitary or multiple, seen in distal part of nerve
• Microscopic: interlacing bands of spindle cells w/ elongated nuclei
• Infiltrate nerve and are difficult to separate from nerve bundle, hard to remove
• Can undergo malignant change and infiltrate adjacent tissue

Question 46

Neurofibromatosis Type 1

Diagnosis

Answer 46

Question 47

Malignant Peripheral Nerve Sheath Tumor (MPNST)

Answer 47

• Neoplasms in adults
• Schwann cell derivation and sometimes a clear origin from a peripheral nerve
• May arise from transformation of a neurofibroma, usually plexiform type
  
  • 3% to 10% of all patients w/ NF1 develop a malignant peripheral nerve sheath tumor during their lifetime
• Large, poorly defined masses
• Microscopically tumors are highly cellular and exhibit features of overt malignancy
  
  • Anaplasia, necrosis, infiltrative growth pattern, pleomorphism and high proliferative activity

Question 48

CNS Tumors

Summary

Answer 48

Question 49

Peripheral Nerve Sheath Tumors

Summary

Answer 49