1. Tumors of Neuroepithelial Tissue
Marta E. Couce, MD, PhD

2. Astrocytic tumors VARIANTS Fibrillary Gemistocytic Small cell
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

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

4. 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)

5. 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

6. 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)

7. Diffuse Astrocytoma Clinical: Radiology: Touch Prep/smear:
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

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

9. 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

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

11. I/Glioblastoma (GBM) Clinical Radiology Touch prep/smear
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

12. 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

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

14. Gliosarcoma Clinical Radiology Touch prep/smear Permanent histology
2% of glioblastomas, 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

15. 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)

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

17. 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

18. PXA H&E WITH TYPICAL HISTOLOGY

19. 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)

20. 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

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

22. 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

23. 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

24. 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

25. Ependymoma Clinical Radiology Touch prep/smear Permanent histology
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

26. A B C EPENDYMOMA. A&B:H&E SHOWING PERIVASCULAR
PSEUDOROSETTES. C: GFAP IMMUNOSTAIN

27. 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

28. 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

29. 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

30. A B
MYXOPAPILLARY EPENDYMOMA. A: MRI IMAGE SHOWING
SHARPLY DEMARCATED TUMOR IN THE CONUS MEDULLARIS
B: CUT SECTION OF THE GROSS SPECIMEN

31. Subependymoma Clinical Radiology Touch prep/smear Permanent histology
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

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

33. 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

34. 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

35. 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

36. Astroblastoma Clinical Radiology Permanent histology
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.

37. Gliomatosis Cerebri Clinical Radiology Touch prep/smear
Malignant glial tumor(WHO grade III) that infiltrates the brain extensively both hemispheres, extending to infratentorial structures. Incidence between 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