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

GEMISTOCYTIC ASTROCYTOMA. A:HEMATOXYLIN AND EOSIN (H&E), B: IMMUNOSTAIN FOR GLIAL FIBRILLARY ACIDIC PROTEIN (GFAP)

A B

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

DIFFUSE ASTROCYTOMAA:T1 WEIGHTED IMAGE WITH CONTRASTB: SMEAR

A

B

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 ASTROCYTOMAA:T1 WEIGHTED IMAGE WITH CONTRASTB: 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 CONTRASTB: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)

PILOCYTIC ASTROCYTOMA, A:MRI,T1 WEIGHTED IMAGE WITH CONTRAST, B:SMEAR, C:PERMANENT H&E WITH MYXOID BACKGROUND AND HYALINIZED VESSELS

A

B

C

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

OLIGODENDROGLIOMA. A: MRI FLAIR IMAGE. B: PERMANENT H&E SHOWING UNIFORM ROUND NUCLEI AND ECCENTRIC EOSINOPHILIC CYTOPLASM

A B

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&ESHOWING 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

AB

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 MEDULLARISB: 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 VENTRICLEB: PERMANENT H&E WITH TYPICALHISTOLOGY

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