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