Tumors of Neuroepithelial Tissue

Marta E. Couce, MD, PhD

Astrocytic tumors

•

VARIANTS

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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

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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 DIFFUSE ASTROCYTOMA A:T1 WEIGHTED IMAGE WITH CONTRAST B: SMEAR

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 ANAPLASTIC ASTROCYTOMA A:T1 WEIGHTED IMAGE WITH CONTRAST B: SMEAR

B

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

GBM. A:MRI, T1 WEIGHTED IMAGE WITH CONTRAST B:PERMANENT H&E: NECROSIS WITH NUCLEAR PALISADING B

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 B

C 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, 4 th 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 C B 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

SUBEPENDYMOMA.

A: T1 WEIGHTED MRI IMAGE SHOWING A LARGE TUMOR IN THE RIGHT LATERAL VENTRICLE B: PERMANENT H&E WITH TYPICAL HISTOLOGY B

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