CNS pathology
Epidemiology
The annual incidence of intracranial and intraspinal masses is 24/100.000 people and 1-
2/100000 respectively. Their prognosis is generally unfavorable since 25% are metastatic
at diagnosis. They account for 20% of tumors in childhood, being most frequently located
in the posterior cranial fossa; in adults the most common location are the cerebral
hemispheres above the tentorium. Some brain tumors occur in people with neoplastic
syndromes such as tuberous sclerosis, VHL, NF1, NF2, Cowden syndrome (PTEN, KLLN,
WWP1), Li-Fraumeni syndrome (TP53) etc.
CNS tumors do NOT use TNM staging, since size and location are less important for
prognosis than histological type and grade, as well as Ki67, gene deletion, MGMT
methylation and IDH-1 mutation with or without deletions of 1p19q (for gliomas).
During clinical assessment of the patient, it is important to evaluate location, pattern of
growth (unifocality or multifocality), correlated functional neurological status and extent
of surgical resection because a benign tumor that is large can still lead to clinical deficits
and poor prognosis, being potentially lethal if located in the respiratory centers. The brain
has no lymphatic system so LNs cannot be affected and hematogenous metastatic
spread is rare; CNS tumors usually recur locally, often progressing to a higher histological
grade due to clonal evolution of the tumor and spread regionally through the CSF.
Concerning intraoperative evaluations of CNS tumors, these are based on cytological
smears (with the help of MRI) because frozen sections cannot be done since brain tissue
is rich in water and fat, creating artifacts.
WHO histological-molecular classification (2021)
The new classification for CNS tumors
includes histological criteria,
pathological molecular changes, such as
mutations in the isocitrate dehydrogenase
(IDH) gene and deletion of chromosomal
segments 1p and 19q, because even low
grade tumors can exhibit aggressive
behavior, and grading (I-IV) based on
nuclear atypia, number of mitotic figures,
endothelial cell proliferation (at least 2
layers) and amount of tumor necrosis.
- Grade I: benign, e.g. pilocytic
astrocytoma
- Grade II: relatively slow growing and somewhat infiltrative, e.g. diffuse
astrocytoma, pure oligodendroglioma
- Grade III: malignant and infiltrative e.g. anaplastic oligodendroglioma, anaplastic
astrocytoma
- Grade IV: glioblastoma multiforme, medulloblastoma
,IDH is an enzyme of the Krebs’ cycle that catalyzes the oxidative decarboxylation of
isocitrate to alpha-ketoglutarate and CO2; when mutated or overexpressed, it leads to
an accumulation of 2-hydroxyglutarate and this is the first step in oncogenesis in glial
tumors since the metabolite inhibits enzymes that regulate DNA methylation therefore
causing epigenetic dysregulation (increased methylation). This mutation can be
detected by IHC and is associated to better prognosis w.r.t. IDH wild-type gliomas.
1p-19q codeletion is characteristic of oligodendrogliomas and is associated with better
prognosis and response to chemotherapy (temozolomide and PCV); tumors with deletion
of only one allele have intermediate prognosis.
Gliomas
Gliomas are the most frequent CNS tumor, accounting for 40% of primary intracranial
tumors; they are neuroepithelial tumors that originate from glial cells, including
astrocytes, oligodendrocytes and ependymal cells, the latter constituting the thin
neuroepithelial lining of the ventricular system of the brain and central canal of the spinal
cord. Tumors are thought to arise from progenitor cells that preferentially differentiated
towards one of the cellular lineages. Gliomas may be circumscribed (grade 1) or diffuse
(grades 2-4). Adult-type diffuse gliomas are categorized into 3 types:
- Astrocytoma, IDH mutant (grades II, III, IV)
- Glioblastoma, IDH-wildtype (grade IV): the most frequent (50% gliomas) and
lethal CNS tumor
- Oligodendroglioma, IDH mutatnt and 1p/19q co-deleted (grades II and III).
Astrocytoma
IDH-mutant tumors; are more common in elderly but may occur at any age.
Location: mainly in the cerebral hemispheres, rarely in the spinal cord and cerebellum
Clinical presentation: seizures (most common if low-grade infiltrating), headaches
(signs of raised cranial pressure most common if high-grade), focal neurological deficits
related to the anatomical site of involvement (speech arrest is common).
, Radiology: high grade astrocytomas have abnormally leaky vessels, resulting in a
permeable BBB so contrast enhancement is seen on imaging studies.
Pathogenesis:
- primary driver mutations in IDH1 or less frequently IDH2 – notice that only IDH1
can be detected on IHC so you should perform molecular sequencing if you
suspect IDH2 mutation
- inactivating mutations in TP53 and ATRX (oncosuppressor genes)
IHC: TP53, ATRX, IDH1
Classification
IDH-mutant (diffuse) astrocytoma, grade 2
It is a poorly defined, gray, diffusely, well-differentiated infiltrative
tumor that distorts the brain parenchyma, expanding in size from a
few cm to enormous lesions. Texture may be firm, soft or gelatinous
with cystic degeneration.
Radiology: non-contrast MRI shows a not well-defined mass, that can distort surrounding
structures
Microscopy: cytologically we see markedly elevated
cellularity w.r.t. normal parenchyma; on histology, there is
high cellular density of reactive astrocytes that are irregular
in size and have large, atypical hyperchromatic nuclei and
abundant cytoplasm; cytoplasmic processes extend,
creating a fibrillary background. Vessels are thin, absence of
mitotic figures. Microvascular proliferation, necrosis, and
homozygous deletion of CDKN2A1 and/or CDKN2B are absent.
IHC:
- Glial fibrillary acidic protein (GFAP) +, a marker of astrocytic differentiation.
- Synaptophysin (marker of neuronal differentiation) negative.
- MIB1/Ki67 index is very low, with <1% cells showing positivity since it is a low
grade glioma (still, remember that normally in the brain there is NO
PROLIFERATION).
- IDH1 mutation
- ATRX loss of expression
- p53 positivity in mutated cells
1
CDKs usually promote cellular proliferation by producing unsuppressed p13 and p15.
Epidemiology
The annual incidence of intracranial and intraspinal masses is 24/100.000 people and 1-
2/100000 respectively. Their prognosis is generally unfavorable since 25% are metastatic
at diagnosis. They account for 20% of tumors in childhood, being most frequently located
in the posterior cranial fossa; in adults the most common location are the cerebral
hemispheres above the tentorium. Some brain tumors occur in people with neoplastic
syndromes such as tuberous sclerosis, VHL, NF1, NF2, Cowden syndrome (PTEN, KLLN,
WWP1), Li-Fraumeni syndrome (TP53) etc.
CNS tumors do NOT use TNM staging, since size and location are less important for
prognosis than histological type and grade, as well as Ki67, gene deletion, MGMT
methylation and IDH-1 mutation with or without deletions of 1p19q (for gliomas).
During clinical assessment of the patient, it is important to evaluate location, pattern of
growth (unifocality or multifocality), correlated functional neurological status and extent
of surgical resection because a benign tumor that is large can still lead to clinical deficits
and poor prognosis, being potentially lethal if located in the respiratory centers. The brain
has no lymphatic system so LNs cannot be affected and hematogenous metastatic
spread is rare; CNS tumors usually recur locally, often progressing to a higher histological
grade due to clonal evolution of the tumor and spread regionally through the CSF.
Concerning intraoperative evaluations of CNS tumors, these are based on cytological
smears (with the help of MRI) because frozen sections cannot be done since brain tissue
is rich in water and fat, creating artifacts.
WHO histological-molecular classification (2021)
The new classification for CNS tumors
includes histological criteria,
pathological molecular changes, such as
mutations in the isocitrate dehydrogenase
(IDH) gene and deletion of chromosomal
segments 1p and 19q, because even low
grade tumors can exhibit aggressive
behavior, and grading (I-IV) based on
nuclear atypia, number of mitotic figures,
endothelial cell proliferation (at least 2
layers) and amount of tumor necrosis.
- Grade I: benign, e.g. pilocytic
astrocytoma
- Grade II: relatively slow growing and somewhat infiltrative, e.g. diffuse
astrocytoma, pure oligodendroglioma
- Grade III: malignant and infiltrative e.g. anaplastic oligodendroglioma, anaplastic
astrocytoma
- Grade IV: glioblastoma multiforme, medulloblastoma
,IDH is an enzyme of the Krebs’ cycle that catalyzes the oxidative decarboxylation of
isocitrate to alpha-ketoglutarate and CO2; when mutated or overexpressed, it leads to
an accumulation of 2-hydroxyglutarate and this is the first step in oncogenesis in glial
tumors since the metabolite inhibits enzymes that regulate DNA methylation therefore
causing epigenetic dysregulation (increased methylation). This mutation can be
detected by IHC and is associated to better prognosis w.r.t. IDH wild-type gliomas.
1p-19q codeletion is characteristic of oligodendrogliomas and is associated with better
prognosis and response to chemotherapy (temozolomide and PCV); tumors with deletion
of only one allele have intermediate prognosis.
Gliomas
Gliomas are the most frequent CNS tumor, accounting for 40% of primary intracranial
tumors; they are neuroepithelial tumors that originate from glial cells, including
astrocytes, oligodendrocytes and ependymal cells, the latter constituting the thin
neuroepithelial lining of the ventricular system of the brain and central canal of the spinal
cord. Tumors are thought to arise from progenitor cells that preferentially differentiated
towards one of the cellular lineages. Gliomas may be circumscribed (grade 1) or diffuse
(grades 2-4). Adult-type diffuse gliomas are categorized into 3 types:
- Astrocytoma, IDH mutant (grades II, III, IV)
- Glioblastoma, IDH-wildtype (grade IV): the most frequent (50% gliomas) and
lethal CNS tumor
- Oligodendroglioma, IDH mutatnt and 1p/19q co-deleted (grades II and III).
Astrocytoma
IDH-mutant tumors; are more common in elderly but may occur at any age.
Location: mainly in the cerebral hemispheres, rarely in the spinal cord and cerebellum
Clinical presentation: seizures (most common if low-grade infiltrating), headaches
(signs of raised cranial pressure most common if high-grade), focal neurological deficits
related to the anatomical site of involvement (speech arrest is common).
, Radiology: high grade astrocytomas have abnormally leaky vessels, resulting in a
permeable BBB so contrast enhancement is seen on imaging studies.
Pathogenesis:
- primary driver mutations in IDH1 or less frequently IDH2 – notice that only IDH1
can be detected on IHC so you should perform molecular sequencing if you
suspect IDH2 mutation
- inactivating mutations in TP53 and ATRX (oncosuppressor genes)
IHC: TP53, ATRX, IDH1
Classification
IDH-mutant (diffuse) astrocytoma, grade 2
It is a poorly defined, gray, diffusely, well-differentiated infiltrative
tumor that distorts the brain parenchyma, expanding in size from a
few cm to enormous lesions. Texture may be firm, soft or gelatinous
with cystic degeneration.
Radiology: non-contrast MRI shows a not well-defined mass, that can distort surrounding
structures
Microscopy: cytologically we see markedly elevated
cellularity w.r.t. normal parenchyma; on histology, there is
high cellular density of reactive astrocytes that are irregular
in size and have large, atypical hyperchromatic nuclei and
abundant cytoplasm; cytoplasmic processes extend,
creating a fibrillary background. Vessels are thin, absence of
mitotic figures. Microvascular proliferation, necrosis, and
homozygous deletion of CDKN2A1 and/or CDKN2B are absent.
IHC:
- Glial fibrillary acidic protein (GFAP) +, a marker of astrocytic differentiation.
- Synaptophysin (marker of neuronal differentiation) negative.
- MIB1/Ki67 index is very low, with <1% cells showing positivity since it is a low
grade glioma (still, remember that normally in the brain there is NO
PROLIFERATION).
- IDH1 mutation
- ATRX loss of expression
- p53 positivity in mutated cells
1
CDKs usually promote cellular proliferation by producing unsuppressed p13 and p15.
