Tumors of Neuroepithelial Tissue
Marta E. Couce, MD, PhD
Astrocytic tumors
• VARIANTS
– Fibrillary
• most common, inconspicuous cytoplasm, hyperchromatic nucleus,
– Gemistocytic
• abundant, eosinophilic, rounded, GFAP positive cytoplasm, short cytoplasmic
processes, associated perivascular inflammation, rare mitosis, high rate of
anaplastic transformation
– Small cell
• minimal cytoplasm, hyperchromatic nuclei, high mitotic index. Differential
diagnosis with other small cell malignancies
– Giant cell
• Regressive change?. Normally associated with GBM
– Granular cell
• PAS +, some GFAP+, degenerative pathway?
– Lipidized cell
– Metaplastic
A
B
GEMISTOCYTIC ASTROCYTOMA.
A:HEMATOXYLIN AND EOSIN (H&E), B: IMMUNOSTAIN
FOR GLIAL FIBRILLARY ACIDIC PROTEIN (GFAP)
Astrocytic tumors, Grading schemes
St. Anne-Mayo
-Atypia
-Mitosis (one or more depending on size of biopsy)
-Necrosis
-Endothelial proliferation
grade 1=rare (0 criteria)
grade 2=well differentiated astrocytoma (1 criterion)
grade 3=anaplastic astrocytoma (2 criteria)
grade 4=glioblastoma multiforme (GBM) (3 or 4 criteria)
Astrocytic tumors, Grading schemes
• WHO (2000)
– Diffusely infiltrating astrocytomas
• Diffuse astrocytomas (grade II)
• Anaplastic astrocytoma (grade III)
– Mitotic activity
• Glioblastoma multiforme (grade IV)
– Necrosis or endothelial proliferation
Astrocytic tumors, differential diagnosis
with other entities
• Astrocytoma vs.reactive gliosis
– GFAP shows equally spaced astrocytes with radiating processes. MIB-1
positive in a low % of cells, P53 can also be positive in a % of neoplastic
cells
• Astrocytoma vs. demyelinating process
– LFB shows myelin loss. Bielchowski or Neurofilament IP show relative
axonal sparing, CD-68 shows numerous macrophages, GFAP: reactive
astrocytes
• Recurrent tumor vs. radiation effect
– Coagulative necrosis without pseudopalisading, dystrophic calcification,
vascular hyalinization
• GBM vs. metastasis vs. lymphoma vs. PNET
– CAM5.2 (epithelial marker), S-100 (melanoma, glial), GFAP (glial), LCA
(lymphoid, Synaptophysin (PNET, small cell ca)
Diffuse Astrocytoma
• Clinical:
– 30-40 yo, seizures, insidious onset,death due to infiltration of vital
structures or herniation
– Can transform into higher grade. Survival: 5-8 years
• Radiology:
– Low density, ill defined lesion, epicenter in white matter, non-enhancing
• Touch Prep/smear:
– Mildly hypercellular, fibrillary background, atypia
• Permanent histology:
– Same as above, possible microcysts, clustering, infiltration of cortex
• Genetics:
– TP53 mutations in 60-80%. TP53 protein accumulation correlates with
presence of mutation in 74%
– Other changes: +7q, +8q, LOH 22q, -6
A
B
DIFFUSE ASTROCYTOMA
A:T1 WEIGHTED IMAGE
WITH CONTRAST
B: SMEAR
Anaplastic Astrocytoma
• Clinical
– 40-50 yo, more rapid onset, survival 2-3 years, high rate transformation to
GBM
• Radiology
– Ill-defined mass, low density, may have partial contrast enhancement,
peritumoral edema and mass effect can be present
• Touch prep/smear
– Hypercellular, greater atypia, fibrillary processes, mitosis might be
present
• Permanent histology
– Same as above plus mitotic activity
• Genetics
– High frequency of TP53 mutations, LOH 10q, 19q
A
B
ANAPLASTIC ASTROCYTOMA
A:T1 WEIGHTED IMAGE WITH
CONTRAST
B: SMEAR
I/Glioblastoma (GBM)
•
Clinical
– Most frequent brain tumor, 50—60 yo, rapid onset with functional deficits, survival
commonly less than 1 year
•
Radiology
– Ring enhancing mass, subcortical white matter, variegated, may cross corpus
callosum
•
Touch prep/smear
– Fibrillary processes common, but might not be present, variable pleomorphism,
mitosis, necrosis
•
Permanent histology
– Same as above, plus pseudo-palisading necrosis and/or endothelial proliferation,
infiltrative margin
II/ Glioblastoma (GBM)
•
Genetics
– Primary (de novo): EGFR amplification (>60%), MDM2 over-expression (with and
without gene amplification), p16 deletion, PTEN mutation, LOH 10p and 10q
– Secondary: PDGFR-a amplification, LOH 10q, LOH 19q, LOH 17p
•
Adult vs. pediatric glioblastomas
– Usually develop de novo, 40-50% show TP53 mutations, LOH 10. Low frequency of
EGFR and MDM2 amplification.
•
Predictive factors: (controversial)
–
–
–
–
–
Necrosis: presence and extent correlates with poor prognosis
Resection: greater extent of resection, better prognosis
Age: young age, better prognosis
Proliferation, correlates directly with histologic grade
Genetics:high levels of expression of PTEN/MMAC1 associated with longer survival
A
B
GBM. A:MRI, T1 WEIGHTED
IMAGE WITH CONTRAST
B:PERMANENT H&E:
NECROSIS WITH NUCLEAR
PALISADING
Gliosarcoma
•
Clinical
– 2% of glioblastomas, 40-60 yo, short history, seizures and paresis
•
Radiology
– Well demarcated, hyperdense, homogeneous contrast enhancement
•
Touch prep/smear
– Difficult to smear, atypia, fibrillary background
•
Permanent histology
– Biphasic tissue pattern, with glial and mesenchymal differentiation. Prominent
reticulin deposition in mesenchymal areas (fibrosarcoma-like most common)
•
Genetics
– Similar genetic profile to primary glioblastomas, with the exception of EGFR
amplification
Pilocytic astrocytoma
•
Clinical
– Child/young adult. Cerebellum, hypothalamus, optic nerve, cerebral hemispheres,
spinal cord. Insidious onset, excellent prognosis
•
Radiology
– Bright T1, partially cystic, mural nodule, enhances
•
Touch prep/smear
– Piloid cells (bipolar with ‘hair-like” processes, Rosenthal fibers, eosinophilic
granular bodies, mucinous background
•
Permanent histology
– Same as above plus bizarre multi nucleate cells, glomeruloid vascular proliferation,
“oligo-like” regions, biphasic cellular and loose microcystic change, areas of
infarct. Malignant transformation exceedingly rare
•
Genetics
– Either normal karyotype or a variety of findings: gains of chromosome 22, and
gains or deletions on chromosome 19 more common. Occasionally loss of
17q(including NF1 gene)
A
C
B
PILOCYTIC ASTROCYTOMA,
A:MRI,T1 WEIGHTED IMAGE WITH
CONTRAST, B:SMEAR,
C:PERMANENT H&E WITH MYXOID
BACKGROUND AND HYALINIZED
VESSELS
Pleomorphic xanthoastrocytoma
(PXA)
• Clinical
– Young adult with chronic seizures. Good prognosis. Anaplastic
transformation in 15%
• Radiology
– Cyst with enhancing mural nodule. Commonly superficial and temporal
lobe
• Touch prep/smear
– Difficult to smear (high reticulin content). High degree of pleomorphism
• Permanent histology
– Xanthomatous cells, perivascular lymphocytic cuffing. May undergo
anaplastic transformation
• Genetics
– Some cases with TP53 mutations
PXA H&E WITH TYPICAL HISTOLOGY
Subependymal giant cell astrocytoma
(SEGA)
•
Clinical
– Child/young adult with signs of obstructive hydrocephalus. Epilepsy and autistic
behavior. May be the first manifestation of tuberous sclerosis (TSC). Slow
growing tumor with very good prognosis. The most common CNS tumor in TSC
patients
•
Radiology
– Wall of lateral ventricles. Calcification and hemorrhage might be present. Can
block foramen of Monro and cause hydrocephalus. Other features of TSC can be
present: “candle guttering”, subependymal calcifications, cortical tubers
•
Touch prep/smears
– Large ganglioid astrocytes, difficult to smear
•
Permanent histology
– Circumscribed, calcified tumor with large plump cells showing clustering and
perivascular pseudopallisading. These cells show phenotypes suggestive of mixed
glioneuronal origin.
•
Genetics
– Mutations in TSC1 (9q) and TSC2(16p, more common)
Oligodendroglioma (WHO grade II)
•
Clinical
– 30-40 yo with long history of seizures. Survival is approximately 10 years. Treated
with PCV chemotherapy and/or radiation. Malignant progression less frequent and
/or slower than astrocytomas
•
Radiology
– Cerebral hemisphere, often calcified, with prominent cortical extension. MRI:
hypointense on T1-weighted images, sometimes cystic degeneration
•
Touch prep/smear
– Uniform round nuclei in loose fibrillary background. Calcification, few
cytoplasmic processes.
•
Permanent histology
– Sometimes perinuclear halo artifact, chicken-wire capillary network. Prominence
of secondary structures: perineuronal satellitosis, subpial accumulation.
Microgemistocytes (GFAP positive, smaller than astrocytes, with sharp blunt
demarcation of the cytoplasm
•
Genetics
– LOH 1p, LOH 19q
A
B
OLIGODENDROGLIOMA. A: MRI FLAIR IMAGE.
B: PERMANENT H&E SHOWING UNIFORM
ROUND NUCLEI AND ECCENTRIC EOSINOPHILIC CYTOPLASM
Anaplastic oligodendroglioma (WHO grade III)
•
Clinical
– Adults. Some with pre-op history very short. Others with long-standing signs
(progression?)
•
Radiology
– Heterogeneous patterns (necrosis, cystic degeneration, hemorrhage). Patchy
contrast enhancement
•
Touch prep/smear
– Anaplastic features in a loose fibrillary background
•
Permanent histology
– Anaplastic features can be focal, with increased cellularity, marked cytologic atypia
and high mitotic activity. Microvascular proliferation and necrosis might be
present.
•
Genetics
– LOH of 1p and 19q with additional deletions on 9p and 10. Those with 1p or 1p
and 19q LOH are typically sensitive to PCV chemotherapy and a substantially
prolonged survival
Oligoastrocytoma (WHO grade II)
•
Clinical
– 35-45 yo. Present with seizures, personality changes, paresias, signs of
increased intracranial pressure
•
Radiology
– No special features, similar to oligodendrogliomas. Some are contrast
enhanced
•
Touch prep/smear
– -Mixture of fibrillary background and dense cellularity with areas with a
loose, sometimes myxoid background and relatively uniform round
neoplastic cells
•
Permanent histology
– Can be biphasic, with distinct areas of oligodendroglial and astrocytic
differentiation; or intermingled variant withy both components intimately
admixed
•
Genetics
– 30-50% associated with LOH on 1p and 19q. 30% with LOH on 17p. Some
show a mixture of findings
Anaplastic oligoastrocytoma
(WHO grade III)
•
Clinical
– Mean age 45. Predominantly frontal lobe. Short or long clinical history,
suggesting a pre-existing low grade glioma in the latter
•
Radiology
– No significant differences from anaplastic oligos. They may be contrast
enhanced
•
Touch prep/smear
– High degree of anaplasia and pleomorphism in a predominant fibrillary
background
•
Permanent histology
– Evidence of high mitotic activity, microvascular proliferation or necrosis can
be seen in one or both components. There is prominent nuclear atypia and
pleomorphism
•
Genetics
– LOH on 9p, 10 and 11p have been described
Ependymoma
•
Clinical
– All age groups. Periventricular, supratentorial, 4th ventricle, spinal cord. Clinical
behavior is difficult to predict. Spinal and supratentorial ependymomas have better
prognosis. Manifestations are localization dependent
•
Radiology
– Well circumscribed lesions with different degrees of contrast
enhancement.Calcification, cysts and hemorrhage occasional.
•
Touch prep/smear
– Uniform round nuclei in fibrillary background. Bland chromatin, sometimes
prominent nucleoli. Perivascular pseudorosettes
•
Permanent histology
– Same as above plus ependymal true rosettes, ependymal canals. Sharp demarcation
with adjacent parenchyma. EM might be needed for diagnosis: cilia, microvilli,
junctional complexes
– Variants: Classic, Cellular, Clear cell, papillary, myxopapillary, Tanycitic
•
Genetics
– 30% associated with aberrations on chromosome 22
A
B
C
EPENDYMOMA. A&B:H&E
SHOWING PERIVASCULAR
PSEUDOROSETTES. C: GFAP
IMMUNOSTAIN
Anaplastic Ependymoma
•
Clinical
– Similar to ependymomas, but develop more rapidly. More common in
intracranial location, particularly posterior fossa. Incomplete resection and
CSF spread are signs of poor outcome.
•
Radiology
– Contrast enhancement
•
Touch prep/smear
– Same features as ependymomas. High degree of anaplasia. Mitosis can be seen
•
Permanent histology
– Increased cellularity associated with brisk mitotic activity. Microvascular
proliferation and pseudopallisading necrosis. Perivascular pseudorosettes
usually seen. Relatively well demarcated. GFAP expression might be reduced.
•
Genetics
– LOH 10q can be seen in some cases
A
B
ANAPLASTIC EPENDYMOMA A: H&E SHOWING
NECROSIS WITH PALISADING. B: IMMUNOSTAIN WITH THE
PROLIFERATING MARKER KI-67 DEMONSTRATING MORE THAN
50% OF POSITIVE CELLS
Myxopapillary ependymoma
• Clinical
– Slow growing tumors in young adults, located in the conus-cauda-fillum
terminale of spinal cord. Back pain of long duration
• Radiology
– MRI: sharply circumscribed lesion with enhancement
• Touch prep/smear
– Uniform round nuclei in a loose fibrillary background with myxoid foci
• Permanent histology
– Cuboidal cells radially arranged in papillary formations around
vascularized stromal cores. Prominent mucoid matrix and microcysts.
• Genetics
– No systematic molecular studies
A
B
MYXOPAPILLARY EPENDYMOMA. A: MRI IMAGE SHOWING
SHARPLY DEMARCATED TUMOR IN THE CONUS MEDULLARIS
B: CUT SECTION OF THE GROSS SPECIMEN
Subependymoma
•
Clinical
– Middle age and elderly men more common. Can be incidental or cause ventricular
obstruction and raised intracranial pressure
•
Radiology
– Sharply demarcated, nodular tumors of varying size, non-enhancing. Can be
calcified
•
Touch prep/smear
– Ependymal nuclear features, foci of myxoid background, clustering of nuclei
•
Permanent histology
– Lobulated, demarcated. Mixture of astrocytes and ependymal cells. Paucicellular
with prominent clustering. Highly fibrillary background resembling astrocytoma.
Microcysts with myxoid content
•
Genetics
– Consistent genetic aberrations have not been found
A
B
SUBEPENDYMOMA.
A: T1 WEIGHTED MRI IMAGE
SHOWING A LARGE TUMOR IN
THE RIGHT LATERAL VENTRICLE
B: PERMANENT H&E WITH
TYPICAL
HISTOLOGY
Choroid Plexus Papilloma
•
Clinical
– 80% lateral ventricular tumors occur in patients younger that 20 years. Forth
ventricular tumors are evenly distributed in all age groups. Present with signs of
hydrocephalus and raised intracranial pressure
•
Radiology
– Intraventricular hyperdense and contrast enhancing mass
•
Touch prep/smear
– Cuboidal/columnar, monomorphic cells with papillary formations. Necrosis might
be present
•
Permanent histology
– Papillary formations, with uniform cuboidal/columnar cells lining fibrovascular
cores. No prominent mitotic activity or brain invasion is seen. They express
thransthyretin, cytokeratin and vimentin. Variably S-100 positive
•
Genetics
– Hyperploidy, with gains on chromosomes: 7,9,12,15, 17 and 18
Choroid plexus carcinoma
• Clinical
– 80% in children
• Radiology
– Same as papilloma
• Touch prep/smear
– Same as papilloma but higher degree of atypia, pleomorphism. Mitosis
and necrosis are usually identified
• Permanent histology
– Can be largely solid. Nuclear pleomorphism, mitosis, large necrotic areas
and diffuse brain invasion
• Genetics
– Hyperploidy, with gains on chromosomes: 7,9,12,15, 17 and 18
Chordoid glioma of third ventricle
• Clinical
– Rare, slow growing, in anterior portion of third ventricle. Signs of
obstructive hydrocephalus
• Radiology
– Well circumscribed, uniformly enhancing. Often attached to hypothalamus
and suprasellar structures
• Permanent histology
– Clusters and cords of epithelioid tumor cells in a mucinous stroma with
variable lymphoplasmacytic infiltration (differential diagnosis with
chordoid meningioma.Mitosis are rare. Tumor cells are positive for GFAP
and vimentin. EMA can be seen focally
Astroblastoma
• Clinical
– Very rare, unknown origin, young adults. Good prognosis if totally
resected
• Radiology
– Cerebral hemispheres, optic nerves, corpus callosum, cerebellum…Well
defined lesions, often enhancing
• Permanent histology
– Perivascular pseudorosette pattern of pleomorphic GFAP positive cells,
with broad processes radiating towards a central vessel with hyalinized
walls. High degree variants show multiple layers, atypia, mitosis and
hyperplasia of endothelial cells. Necrosis is seen in low and high grade
types. S-100 and vimentin are often positive.
Gliomatosis Cerebri
•
Clinical
– Malignant glial tumor(WHO grade III) that infiltrates the brain extensively both
hemispheres, extending to infratentorial structures. Incidence between 40-50 yo.
Corticospinal tract deficiencies, headache, dementia, seizures
•
Radiology
– Extensive white and gray matter involvement with a diffuse pattern. T2 weighted
image reveals hyperintense diffuse signal with enlargement of the cerebral
structures
•
Touch prep/smear
– Hypercellular, with fibrillary background and scattered atypical elongated glial
cells
•
Permanent histology
– Histologic variation even within same neoplasm. Largely composed of elongated,
hyperchromatic glial cells infiltrating white matter and cortex. Mitotic activity
varies. No necrosis or microvascular proliferation
•
Genetics
– Numerous deletions and extra chromosomes have been described, involving
chromosomes 6, 14, 15, 18, 19 and 20