Which grade of tumor is considered infiltrative?
In which decade of life are Grade II, III, and IV Astrocytomas found?
- Grade II: usually 3rd-4th decase
- Grade III: usually 5th decade
- Grade IV: usually 6th decade and beyond
Pilocytic Astrocytomas generally occur during what decades of life?
Where in brain do they typically occur?
- First 2 decades of life
- Cerebellum and floor/walls of 3rd ventricle, occasionally cerebral hemispheres
What grade of tumor is a Pilocytic Astrocytoma?
What are the distinguishing morphological characteristics of Pilocytic Astrocytomas?
- Well-circumscribed, often CYSTIC w/ a mural nodule
- Biphasic pattern
- Hair-like cells w/ long bipolar processes
- Rosenthal fibers
- Eosinophilic granular bodies (EGBs)
Which disease predisposes patients to Pilocytic Astrocytomas and due to what?
NF-1 due to functional loss of neurofibromin
Which 3 tumors are part of the Glioma family?
Most common presenting signs and symptoms of Infiltrating Astrocytomas?
Seizures, headaches, and focal neurologic deficits related to the site of involvement
Which type of infiltrating astrocytoma belongs to the Grade II-IV designation?
Grade II: diffuse astrocytoma
Grade III: anaplastic astrocytoma
Grade IV: glioblastoma (this is malignant)
Among the higher grade astrocytomas, presence of what mutation is associated with a better outcome?
Mutant form of IDH1
Tumor where the predominant neoplastic astrocyte has a brightly eosinophilic cell body from which emanante abundant, stout processes describes what?
What is the histologic pattern characteristically produced by Glioblastomas?
Pseudo-palisading: tumor cells collecting along the edges of necrotic regions
Necrosis in glioblastoma often occurs in a ________ pattern in areas of hypercellularity
Which additional features differentiate a glioblastoma from anaplastic astrocytomas?
Necrosis and vascular (glomeruloid type)/endothelial cell proliferation
What characteristic of Glioblastomas is seen on MRI?
Which tumor often crosses the corpus callosum and produces a “butterfly” appearance
Contrast ring enhancing lesions, with hypodense central necrosis is characteristic of what kind of tumor?
Alterations in what signaling pathway have been found in Pilocytic Astrocytomas?
BRAF signaling pathway
Which brain tumor appears as a cystic mass with a mural nodule?
Which tumor is most often found in the temporal lobe in children and young adults, usually with a history of seizures?
What distinguishes a Pleomorphic Xanthoastrocytoma from more malignant types?
What is the grade and prognosis of this tumor?
- Abundant reticulin deposits, absence of necrosis and mitotic activity
- Grade II/IV w/ 5-year survival rate of 80%
What is the most common Brainstem Glioma?
Intrinsic pontine glioma
What is the prognosis of Intrinsic Pontine Gliomas?
Aggressive and short survival (most common brainstem gliomas)
When are Oligodendrogliomas most commonly seen (decades)?
How are they graded?
- Most common in fourth and fifth decades
- Grade II/IV
Where in the brain are Oligodendrogliomas most often seen?
Cerebral hemispheres w/ predilection for white matter
What are the most common mutations seen in Oligodendrogliomas; which have a better prognosis?
- IDH1 and IDH2 (better prognosis)
- 1p19q (favorable prognosis)
What are the distinguishing morphological characteristics of Oligodendrogliomas?
- Perinuclear halos, “fried eggs” and delicate anastomosing capillaries, “chicken wire”
Which features distinguish an Anaplastic Oligodendroglioma (III/IV) from an Oligodendroglioma?
Vascular hypertrophy, necrosis, and nuclear anaplasia
During which decades of life are Ependymomas most commonly seen and where are they most commonly located?
- First 2 decades
- Fourth ventricle = most common site
- Spinal cord = most common for adults
When Ependymomas occurs in adults they are most often associated with what other condition; due to what mutation?
NF2 – due to mutation on chromosome 22
Which chromosome is the NF2 gene found on?
Well circumscribed tumors in the brain that often have cysts, focal hemorrhage, and calcification generally describes?
What are the 2 seperate subtype of Ependymomas and which is more serious?
- Mesenchymal subtype = younger patients, more likely to develop metastases w/ a worse prognosis
- Second w/ aberrations of large regions of chromosomes, but have better prognosis
A tumor displaying uniform populations of cells w/ round or oval nuclei w/ abundant clumped chromatin and the appearance of perivascular rosettes is often what type?
Which rosette type found in ependymomas are more diagnostic?
Ependymal rosettes (true rosettes) = MORE diagnostic than perivascular rosettes
What is the grade for most Ependymomas?
Which tumor type is often found in the filum terminale of the spinal cord?
What is a frequent clinical manifestation of posterior fossa ependymomas?
Hydrocephalus (non-communicating) secondary to progressive obstruction of the 4th ventricle
Which location of ependymomas have the worst overall prognosis in children?
- Posteior fossa = worst overall prognosis; 5 year survival is 50%
- Completely resected supratentorial and spinal types are better
Homer-Wright rosettes are most often seen with what 2 brain tumors?
Choroid plexus papillomas are most often found where in children and adults?
- In children – lateral ventricles
- In adults – fourth ventricle
Who is most often affected by Non-neoplastic Colloid Cysts of the 3rd Ventricle?
What is the clinical manifestation?
- Young adults
- Found attached to roof of 3rd ventricle, can obstruct foramina of Monro = non-communicating hydrocephalus
- Can be rapidly fatal
What is an important clinical symptom of Colloid Cysts of the 3rd Ventricle?
Headache, sometimes positional (worse when standing up)
What is the most common neuronal type of tumor in the CNS?
Common activating mutation?
- Mutations in BRAF
Gangliomas are typically ________ lesions that present with ______
Gangliomas are typically superficial lesions that present with seizures
Gangliogliomas are most commonly found in the _______ lobe and have a _____ component
Gangliogliomas are most commonly found in the temporal lobe and have a cystic component
Which low-grade neuronal neoplasm is characterized by evenly spaced, round, uniform nuclei and often islands of neuropil?
What is the most common malignant embryonal CNS tumor in children?
Medulloblastomas are often located where?
Midline of the Cerebellum
Medulloblastomas that occur in older children tend to have what genetic mutations?
- Mutations in WNT signaling pathway
- Monosomy of chromosome 6
- Nuclear expression of β-catenin
What is the prognosis of the WNT type of medulloblastomas?
Best prognosis: with 90% 5-year survival
Medulloblastomas with the second best prognosis, behind the WNT type, tend to occur in infants-young children and are associated with what mutations?
- Mutations in SHH pathway
- May also have MYCN amplification
Group 3 medulloblastomas (worst prognosis) tend to occur in infants-young children and are associated with what mutations?
- MYC amplification
- Isochromosome 17 (i17q)
What are the mutations associated with group 4 Medulloblastomas and what is the prognosis?
- i17q cytogenic alterations, classic or large cell histology
- WITHOUT MYC amplification
- Sometimes with MYCN amplification
- Intermediate prognosis, in general i17q signals a worse prognosis
Which variant of medulloblastomas is characterized by areas of stromal response marked by collagen and reticulin deposition that form pale islands with more neuropil and neuronal markers?
Nodular desmoplastic type
What is a common complication due to Medulloblastomas propensity to form linear chains and infiltrate?
- May infiltrate cerebral cortex and penetrate the pia, spreading into subarachnoid space
- Dissemination through CSF is common complication, giving rise to nodular masses some distance from the priamry tumor (i.e., as far as the cauda equina) – Drop Metastases
How well do Medulloblastomas respond to treatment?
- Exquisitely radiosensitive
- Total excision and irradiation, 5 year survival of 75%
What are CNS supratentorial primitive neuroectodermal tumors (CNS PNET)?
A distinct type of tumor that is poorly differentiated and resembling a medulloblastoma
Atypical Teratoid/Rhabdoid Tumors are most commonly seen in whom and where are they seen in the brain?
Benign or malignant?
- Highly malignant tumor (grade IV) of young children (most often before age 5)
- Posterior fossa and supratentorial compartments
Which chromosome is most often altered in Atypical teratoid/Rhaboid tumors and is considered a hallmark; what specific gene?
- Chromosome 22
- Deletion of the locus and loss of nuclear staining for INI1 protein seen in majority
Cytoplasm of rhaboid cells found in Rhaboid tumors is immunoreactive for what?
- Epithelial membrane antigen
*Other markers may include: smooth muscle actin and keratins
What is the most common CNS neoplasm in immunosuppressed patients, such as those with AIDS or following transplantation?
Primary CNS lymphoma
Vast majority of primary brain lymphomas are of _____origin (immune cell)
In the setting of immunosuppression, the cells in nearly all primary brain lymphomas are latently infected by which virus?
In the setting of organ transplantation, may be associated with a systemic what?
- Epstein-Barr virus
- Systemic post-transcriptional lymphoproliferative disorder
When not associated with immunosuppression, primary CNS lymphomas show a phenotype typical of __________ differentiation
Postgerminal center B-cell differentiation
What is the morphology of the lesions associated with Primary CNS Lymphomas?
Which stain shows their characteristic pattern?
- Frequently mutliple and often involve deep gray matter as well as white matter and cortex; accumulate around vessels
- Reticulin + silver stain show infiltrating cells separated from one another in a pattern called “hooping.”
Primary brain germ cell tumors occur along where?
Most commonly in what locations?
- Along the MIDLINE!
- Most commonly in the pineal (male predominance) and suprasellar regions
During what decades do the majority of Primary Brain Germ Cell tumors occur and who is affected the most?
- 90% during first 2 decades
- Japanese have highest incidence
Germ cell tumors in the pineal region show a strong predominance in which sex?
Which markers of CNS germ cell tumors may be helpful in assisting with diagnosis and tracking response to therapy?
- β- hCG
Metastasis of which type of germ cell tumor to the CNS is common?
What is the significance of this in regards to classifying the tumor?
Gonadal germ cell tumors
*Why the presence of a non-CNS primary tumor must be excluded before a diagnosis of primary germ cell tumor of the CNS is made!
The tumor that is histologically similar to a seminoma in the testis is reffered to what in the CNS?
What is the response of primary brain germ cell tumors to radiation therapy/chemotherapy?
Differentiate Pineocytomas from Pineoblastomas in regards to grade and and who they most commonly affect.
- Pineocytomas = LOW grade and more common in adults
- Pineoblastomas = HIGH grade and more common in kids
Pineoblastomas occur with increased frequency in individuals with which germ line mutations?
Germ line mutations in RB
What is the most common pineal tumor?
What is a risk factor for the development of Meningiomas?
Prior radiation therapy to the head and neck, typically decades earlier
What is the severity of Meningiomas, who are they commonly seen in and where are they found?
- Benign tumors of adults
- Usually attached to the dura; found along any of the external surfaces of the brain as well as ventricular system
What is the most common cytogenic abnormality seen in Meningiomas?
- Loss of chromosome 22, especially the long arm (22q)
- Including the region that harbors the NF2 gene, which encodes the protein merlin
Higher grade Meningiomas are associated with what mutations?
NF2 mutations, loss of chromosome 22, and evidence of chromosomal instability
What is the most common mutation seen in Meningiomas without NF2 mutations?
What is the histologic grade of this type?
- TNF-receptor associated 7 (TRAF7)
- Lower histologic grade
Which tumors are often seen growing en plaque, in which the tumor spreads in a sheet like fashion along the surface of the dura?
Which tumor of the CNS is characterized by whorled clusters of monotonous cells; psammoma bodies?
Which subtype of Meningiomas has PAS+ intracytoplasmic droplets?
Is associated with mutations in what genes?
- Secretory subtype
- TRAF7 and KLF4 genes
What is the typical patient presentation for a Meningioma?
Present with vague non-localizing signs and symptoms or with focal findings due to compression of underlying brain
Which receptors may be expressed by Meningiomas and which patient population can this potentially affect?
- Progesterone and Estrogen receptors
- Pregnancy increases symptomatic presentation NOT incidence
What are the 5 most common primary sites for potential metastasis to the brain?
- Skin (melanoma)
Which rare tumor has a high likelihood of metastasing to the brain?
Where in the CNS is a frequent site of involvement for metastatic disease?
- Intraparenchymal = Gray/White junction
Meningeal carcinomatosis with tumor nodules studding the surface of the brain, spinal cord, and intradural nerve roots is most commonly associated with carcinoma of the _______ and _______.
Lung and Breast
What are the common histologic findings of metastases to the CNS?
Nodules of tumor, often with central areas of necrosis, surrounded by reactive gliosis
Subacute cerebellar degeneration (paraneoplastic syndrome) is associated with destruction of which structures?
- Destruction of Purkinje cells, gliosis, and a mild chronic inflammatory cell infiltrate
- PCA-1 antibody (anti-Yo)
- Women w/ ovarian, uterine, or breast carcinoma
Which antibody is most commonly associated with small cell carcinoma of the lung and may cause limbic encephalitis (paraneoplastic)?
ANNA-1 antibody (anti-Hu) recognized neuronal nuclei in the CNS and PNS
Which antibody is most commonly associated with ovarian teratomas and may cause limbic encephalitis (paraneoplastic)?
NMDA receptor antibody cross-reacts with hippocampal neurons
Which antibody is most commonly associated with peripheral neuropathy and may cause limbic encephalitis (paraneoplastic)?
VGKC-complex antibody: voltage-gated potassium channel
What is an important consideration in regards to limbic encephalitis and malignancy?
The syndrome appears before any malignancy is suspected
Opsoclonus (eye movement disorder) in children is most commonly associated with what malignancy?
Lambert-Eaton myasthenic syndrome is caused by antibodies against?
Voltage-gated calcium channels in the presynaptic elements of the NMJ
What is the treatment for some of the paraneoplastic syndromes and in general which are the best responders?
- Immunotherapy (removal of circulating antibodies and immunosuppression)
- Those with plasma membrane-reactive antibodies (i.e., VGKC and NMDAR) respond better
Cowden syndrome is associated with what tumor; due to what mutation?
- Dysplastic gangliogliocytoma of the cerebellum (Lhermitte-Duclos disease)
- Mutations in PTEN resulting in PI3K/AKT signaling pathway activity
Li-Fraumeni syndrome is associated with what tumor; due to what mutation?
- Mutations in TP53
Turcot syndrome is associated with what tumor; due to what mutation?
- Medulloblastoma or Glioblastoma
- Mutations in APC or mismatch repair genes
Gorlin syndrome is associated with what tumor; due to what mutation?
- Mutations in PTCH gene – upregulation of SHH signaling pathways
What is the inheritance pattern for Tuberous Sclerosis Complex?
Tuberous Sclerosis Complex is characterized by the development of what?
Most frequent clinical manifestations are?
- Development of hamartomas and benign neoplasms involving the brain and other tissues
- Seizures, autism, and mental retardation
What are the 2 tuberous sclerosis locuses; associated chromosome; and protein each encodes
Which is more commonly mutated?
- TSC1 on chromosome 9q34 encodes hamartin
- TSC2 on chromosome 16p13.3 encodes tuberin = Most commonly mutated
Which tumors are associated with the Tuberous Sclerosis Complex?
- Renal angiomyolipomas
- Cardiac rhabdomyomas
- Giant-cell astrocytomas
What are the cutaneous lesions associated with the Tuberous Sclerosis Complex?
- Shagreen patches (localized cutaneous thickenings)
- Ash-leaf patches (hypopigmented areas)
What is the function of the proteins hamartin and tuberin produced by the tuberous sclerosis genes?
How does dysregulation of these proteins lead to the histological characterstics of tumors associated w/ tuberous sclerosis?
- Inhibit the kinase mTOR
- mTOR is key regulator of protein synthesis and other aspects of anabolic metabolism, including control of cell size
*Tumors associated w/ tuberous sclerosis are remarkable for having voluminous amounts of cytoplasm!
Multiple drop like masses associated with clusters of large tumor cells beneath the ventricular surface that buldge into the ventricular system and are known as candle-guttering is associated with?
Tuberous sclerosis – giant cell astrocytomas
Von Hippel-Lindau Disease is associated with the development of which malignancies?
- Hemangioblastomas of the CNS (cerebellum and retina)
- Renal cell carcinoma
What is the inheritance pattern of Von Hippel-Lindau disease; which gene and chromosome are involved?
What is the function of the protein associated with this gene?
- VHL = tumor suppressor gene on chromosome 3p25.3
- VHL is component of ubiquitin ligase complex that down-regulates HIF-1 –> involved in expression of VEGF and erythropoietin
What is responsible for the polycythemia observed in hemangioblastomas associated with Von Hippel-Lindau Disease?
VHL is involved in regulating expression of erythropoietin —> Polycythemia
What is the mnemonic using VHL for Von Hippel-Lindau Disease?
- V = VHL gene
- H = Hemangioblastoma
- L = Lots of catecholamines = pheochromocytoma
*VHL = 3 letters = RCC (renal cell carcinoma)
*VHL = 3 letters = chromosome 3
Metastasis to the brain by what malignancy does not follow the general rule of having the boundary between tumor and brain parenchuma being well-defined microscopically?
Which CNS tumor is characterized as highly vascular and occuring as a mural nodule associated with a large fluid-filled cyst?
Which stain for hemangioblastomas?
NF1 is more common and is characterized by which malignancies and other findings?
- Neurofibromas of peripheral nerve
- Gliomas of optic nerve
- Pigmented nodules of the iris (L**isch nodules)
- Cutaneous hyperpigmented macules (cafe au lait spots)
NF2 is most commonly characterized by which malignancies?
- Bilateral schwannomas of CN VIII
- Multiple meningiomas
- Gliomas may also occur and are typically ependymomas of the spinal cord