Pathology of CNS(Tumor of CNS)

DR Naila Awal

Classification of CNS tumor

• Primary tumor-• Meninges- Meningioma

• Glial cell- Glioma- Astrocytoma, Oligodendroglioma, Ependymoma

• Embryonal- Medulloblastoma, Neuroblastoma, Teratoma• Blood vessel- Angioma, Angiosarcoma

• Others- Epithelial, Pituitary, Pineal gland tumor.• Secondary tumor- Common- Breast, Lung, GIT, Melanoma

CNS-Tumours

• 70% of childhood CNS tumors arise in posterior fossa• In adult tumors arise within the cerebral hemispheres above the tentorium.

Astrocytoma

• Most Frequent

• Types-Infiltrative & Non infiltrative• WHO Grade (I – IV)

• Increased cellularity• Nuclear Pleomorphism• Mitotic activity• Endothelial proliferation • Necrosis - palisading

• Pilocytic astrocytoma• WHO grade- I/IV• Most common CNS neoplasm of childhood• Relatively benign

• Sites• Commonly cerebellum• MRI-• mural nodule (arrow), cyst wall enhancement (arrowheads).

Gross-

Partially cystic pilocytic astrocytoma of the cerebellum. The tumor forms a typical mural nodule.

• M/E-• Elongated Bipolar cells ( elongated hair like processes)• Rosenthal fibers with eosinophilic protein droplets•  mural nodule may be highly vascular; often calcifications• Vascular changes are common – glomeruloid vascular proliferation and vascular hyalinization

• Rosenthal fibers-

tapered corkscrew-shaped,brightly eosinophilic, hyaline masses

• Positive stains• GFAP (strong), PTAH, PAS (protein droplets), alpha-1-antichymotrypsin (protein

droplets)• Neoplastic astrocytes have intermediate cytoplasmic filaments. These filaments, has protein-glial

fibrillary acidic protein (GFAP), can be detected by I/H/C

• GFAP- positive

• D/D-• Diffuse astrocytoma-Age 30-40, site-cerebral hemisphere, Diffuse infiltration,

No vascular proliferation• Gliosis-Hypertrophy & hyperplasia of astrocytes• Pleomorphic xanthoastrocytoma cyst-mural nodule architecture• Piloid gliosis: hypocellular, no spongy areas, numerous Rosenthal fibers

• Pleomorphic xanthoastrocytoma• WHO grade II• Occurs in temporal lobes of children and young adults• Gross• Usually cystic• M/E-• Pleomorphic cells (occasional xanthomatous change), • Perivascular lymphocytic cuffing, scattered eosinophilic granular bodies,

reticulin rich network • No necrosis and no mitosis.

Pleomorphic xanthoastrocytoma. Xanthic cells, expressed as vacuolization of the neoplastic cells, are shown (arrow).

• Positive stains• GFAP and S100 • Reticulin, class III beta tubulin (73%)• Variable expression of neuronal markers including synaptophysin

• D/D-• Glioblastoma and giant cell glioblastoma• Malignant fibrous histiocytoma• Other cystic lesions, especially those with a cyst-mural nodule

architecture (pilocytic astrocytoma and ganglioglioma

Infiltrative astrocytoma

• Site-Infiltrative astrocytomas are usually found in the cerebral

hemispheres, • Age- most common in patients between 30 and 60.• Presentation- Patients most commonly present with seizures, headaches, and

focal neurologic deficits (depending on where the tumor is).

Infiltrating astrocytoma

Grade-II/IV

Diffuse astrocyto

ma

Grade-IV/IV

Glioblastoma

• Diffuse astrocytoma• Most common adult tumor.• 80% of adult primary brain tumors• Location: Usually supratentorial• Age-4th to 6th decades • MRI- • Ill defined, non enhancing lesion with mass effect and variable peritumoral

edema.

• Gross-Poorly defined infiltrative tumor that distorts the brain.

C/S-Firm / soft & gelatinous, Cystic degeneration

• M/E-• Mild to moderate glial cellularity• Variable nuclear pleomorphism• Fibrillary background due to astrocytic process

Diffuse astrocytoma characterized by modest hypercellularity, nuclear pleomorphism, and numerous small microcysts

• Special stain-• GFAP-positive astrocytic cell processes

• Anaplastic astrocytoma• Grading: WHO grade III/IV

● Age and sex: mean age 45 years; male predominance● Site: usually supratentorial, but can be anywhere in CNS; ● MRI: 

• Usually heterogeneous or patchy enhancement

Gross-Anaplastic astrocytoma predominantly occupying the right temporal lobe. The tumour is ill-defined and appears as a homogeneous mass.  Note the large cyst in the periphery of the neoplasm and shift of midline structures towards the left hemisphere.

This astrocytoma had densely cellular areas with back-to-back nuclei, moderate nuclear pleomorphism, and increased mitotic activity. However, necrosis or endothelial proliferation - the two hallmarks of Glioblastoma - were absent.

• M/E-• Increase in cellularity • Nuclear pleomorphism • Hyperchromasia • May have mitosis • No necrosis

• D/D-● Anaplastic oligodendroglioma: • hypercellular with loosely cohesive and single cells, moderate

pleomorphism, vacuolated background, mitotic activity● Anaplastic oligoastrocytoma:

• conspicuous oligodendroglioma and astrocytoma components• Glioblastoma

• Anaplastic astrocytoma Glioblastoma• Increase in cellularity Dense cellularity

• Nuclear pleomorphism • Hyperchromasia • May have mitosis Mitosis • No necrosis Necrosis & vascular proliferation

Gemistocytic astrocytomaDense eosinophilic cytoplasm & eccentrically displaced nucleus. Gemistocytes are frequently found in other fibrillary astrocytomas & oligodendrogliomas. Some authors require at 20% of tumor cells to be gemistocytic before using the designation of gemistocytic astrocytoma. This tumor appears to be composed of an almost pure population of gemistocytic cells.

• Positive stains• GFAP, • Vimentin

• D/D-• Gliosis:• Hypertrophy of cells rather than hyperplasia, even distribution• Subependymal giant cell tumor: intraventricular, larger nuclei,

non-infiltrative• Ganglioglioma: neoplastic neurons

• Glioblastoma• WHO grade IV• "Multiforme" due to variegated gross appearance (firm white areas, yellow necrotic

areas, hemorrhagic areas and cystic areas) as well as diverse histological features• Sites• Usually supratentorial;• Either primary (de novo, with with p53 mutation) or secondary (transformed from

grade II/III astrocytoma)• MRI• Contrast enhancing (ring pattern), • large surrounded by peritumoral edema.• (parietal lobe)

• Gross- glioblastoma is a poorly defined intra-axial mass with variegated (multiform) appearance due to necrosis and hemorrhage. 

• A 9.0 cm tumor with foci of hemorrhage and necrosis involving the left temporal lobe.

• M/E-

• M/E-• Densely cellular with nuclear pleomorphism • Necrosis in a serpentine pattern• Tumour cells crowded along the edges of necrosis - pseudopalisading• When vascular cell proliferation is extreme, the tuft forms a ball-like structure, the glomeruloid body

• Besides necrosis with nuclear pseudopalisading, the presence of endothelial proliferation is another histologic hallmark of glioblastomas.

• Positive stains• GFAP, vimentin, S100, AE1-AE3 (>95%)• Differential diagnosis

• Lymphoma: angiocentric and angioinvasive patterns, no fibrillary background, CD45+

• Meningioma, malignant: EMA+, may contain entrapped GFAP+ glia

• Metastatic carcinoma: discrete, no fibrillary background, GFAP-, CAM5.2+

• Giant cell glioblastoma (IV/IV)• M/E-• Abundant bizzare appearing tumor giant cell, many MNG cell• Extensive necrosis, mitosis

• Gliomatosis Cerebri-• WHO Grade- III/IV• Neoplastic astrocyte infiltrates • the multiple region of brain or • in some cases the entire brain .

• H/P-• Largely composed of elongated, hyperchromatic glial cells Mitosis. No necrosis or microvascular proliferation

Prognosis

Diffuse Astrocytoma

(G-II/IV)

Anaplastic Astrocytoma

(G-III/IV)

Glioblastoma(G-IV/IV)

Oligodendroglioma

• WHO grade- II/IV

• Gross• well-circumscribed, gelatinous,gray masses, often with cysts, focal hemorrhage,& calcification

• M/E-• Sheets of regular cells with spherical nuclei & perinuclear halo (fried egg)(perinuclear halo artifact due to fixation,

and is not present in frozen sections)• Calcifications-90% cases, • Arborizing thin capillaries• (chicken wire pattern)

• Positive stainsOLIG2, Leu7, S100, MAP2 (strong)

• D/D-• Clear cell ependymoma: enhancing, well-circumscribed, perivascualr

pseudorosettes, dot- or ring-like EMA+• Clear cell meningioma: extra-axial, enhancing, PAS+, EMA+

• Metastatic clear cell carcinoma: enhancing, well-circumscribed, EMA+, CK+; molecular testing for 1p/19q deletion may be helpful, but some oligodendrogliomas are negative for the deletion

• Pituitary adenomas: chromogranin+, pituitary hormone+

• Anaplastic oligodendroglioma• WHO grade -III/IV• M/E-• Increased cellular density• Nuclear atypia• Mitosis• Necrosis

• D/D-Metastatic carcinoma:

• Renal cell carcinoma is EMA+,• usually no calcifications

Ependymoma

• Slowly growing tumor of ependymal cells arising from walls of ventricles or spinal canal

• Grade II/!V• MRI-• Well circumscribed lesions with variable enhancement

• Gross-• Typically solid or papillary masses extending from4th ventricle

• M/E-•  Tumor cells resemble normal ependymal cells with round to oval nuclei &

abundant granular chromatin.• Rosette & Perivascular pseudorosette

• Fig- Ependtmoma with true rosette

• True rosette

• Pseudorosette--------------

• D/D-

Glioma:• no true rosettes, • no cell-cell junctions, • no intracytoplasmic microvilli-lined lumina

Anaplastic Ependymoma

• Grade- III /IV• Rare; usually infants and children• Cerebrum/ cerebellum of children / young adults, but all ages and locations• M/E-Marked hypercellularity, nuclear atypia high mitosis & necrosis

Myxopapillary ependymoma

• Grade - I / IV • M/E-• Well differentiated Cuboidal to elongated tumor cells arranged around the

papillary cores with a myxopapillary appearance.• Usually no atypia,• no/low mitotic activity

MOLECULAR CHANGES IN ASTROCYTOMA-GLIOBLASTOMA

• Isocitrate dehydrogenase (IDH)• IDH is a citric acid cycle enzyme that catalyzes that convert isocitrate to a-

ketoglutarate.• IDH1 and IDH2 are frequently mutated in gliomas.• IDH1 mutated in 70-80% of grade II and III astrocytomas,

oligodendrogliomas, oligoastrocytomas, & in secondary but not primary glioblastomas.

• IDH2 mutations are more common in oligodendrogliomas• Detection of IDH1 mutations by I/H/C is an important tool in the diagnosis of

gliomas.

• Tumor Protein 53 (TP53)• It repairs DNA damage and induces apoptosis when damage

cannot be repaired. Its mutation promotes tumor formation •  TP53mutations common in diffuse astrocytoma, anaplastic

astrocytoma, and secondary glioblastoma, and help distinguish glioma from gliosis.

• Mutations can be detected by I/H/C shows strong nuclear staining for p53. 

• Epidermal Growth Factor Receptor (EGFR) Overexpression of EGFR, on 7p, occurs in 40 % of glioblastomas (more commonly primary ones) and less frequently in lower grade astrocytomas .