Pathology (CNS tumors)

• Children 70% infratentorial (pos.fossa)
• Adult 70% supratentorial

True

Glioma include astrocytomas, oligodendrogliomas, and ependymomas

infiltrating astrocytomas and non-infiltrating neoplasms, of which the most common are the pilocytic astrocytomas

Infiltrating Astrocytomas

• These account for about 80% of adult primary brain tumors in adults.
• Usually found in the cerebral hemispheres,
• The most common presenting signs and symptoms are seizures, headaches, and focal neurologic deficits.
• Diffuse astrocytoma (grade II/IV) / anaplastic astrocytoma (grade III/IV) toglioblastoma (grade IV/IV).

• Poorly defined, gray, infiltrative tumor that expands and distorts the invaded brain
• Infiltration beyond the outer margins is always present
• Mild to moderate increase in glial cellularity, variable nuclear pleomorphism, and an intervening feltwork of fine, GFAP-positive astrocytic processes that give the background a fibrillary appearance
•  Diffuse astrocytoma. A, The right frontal tumor has expanded gyri, which led to flattening (arrows). B, There is bilateral expansion of the septum pellucidum by gray, glassy tumor.

Anaplastic astrocytomas show regions that are more densely cellular and have greater nuclear pleomorphism; mitotic figures are often observed

predominant neoplastic astrocyte shows a brightly eosinophilic cell body from which emanate abundant, stout processes

• Variation in the gross appearance of the tumor from region to region
• Similar to anaplastic astrocytoma with the additional features of necrosis  and vascular  or endothelial cell proliferation
• Serpentine pattern of necrosis in areas of hypercellularity
• Tumor cells collect along the edges of the necrotic regions, producing a histologic pattern referred to as pseudo-palisading
• Vascular cell proliferation is characterized by tufts of piled-up cells that bulge into the lumen; the minimal criterion for this feature is a double layer of endothelial cells.
• With marked vascular cell proliferation the tuft forms a ball-like structure, the glomeruloid body
• VEGF, produced by malignant astrocytes in response to hypoxia, contributes to this distinctive vascular change
• Ring enhancement
• Foci of necrosis with pseudopalisading of malignant nuclei and endothelial cell proliferation

VEGF, produced by malignant astrocytes in response to hypoxia, contributes to this distinctive vascular change.

multiple regions of the brain, in some cases the entire brain, are infiltrated by neoplastic astrocytes. Because of the widespread infiltration, this process follows an aggressive course and is considered to be a grade III/IV lesion—independent of the appearance of the individual tumor cells.

combinations of mutations that activate RAS and PI-3 kinase and inactivate p53 and RB

• LG--> mutations affecting p53 and overexpression of platelet-derived growth factor α (PDGF-A) and its receptor.
• The transition to higher grade astrocytoma is associated with disruption of two well-known tumor suppressor genes, RB and p16/CDKNaA, and an unknown putative tumor suppressor on chromosome 19q.

• While primary and secondary glioblastomas show some molecular distinctions, the molecular lesions found in the two types of glioblastoma tend to impinge on the same pathways.
• Whereas secondary glioblastomas usually have p53 mutations, primary astrocytomas more commonly have amplification of MDM2, a gene that encodes an inhibitor of p53.
• While secondary glioblastomas have increased signaling through the PDGF-A receptor, primary glioblastomas often have amplified, mutated epidermal growth factor receptor (EGFR) genes, which encode aberrant forms of EGFR known as EGFRvIII. Both types of mutations lead to increased receptor tyrosine kinase activity and the activation of the RAS and PI-3 kinase pathways

appearance of a more rapidly growing tumor of higher histologic grade

have abnormal vessels that are “leaky”

Methylation of the promoter for the gene encoding the DNA repair enzyme MGMT predicts responsiveness to DNA alkylating drugs—as would be expected since MGMT is critical for the repair of the chemotherapeutically induced DNA modification

• grade I/IV
• Children and young adults
• Usually located in the cerebellum but may also appear in the floor and walls of the third ventricle, the optic nerves

• Cystic
• bipolar cells with long, thin “hairlike” processes that are GFAP-positive and form dense fibrillary meshworks
• Rosenthal fibers and eosinophilic granular bodies
• Tumors are often biphasic with a loose microcystic pattern in addition to the fibrillary areas.
• An increase in the number of blood vessels, often with thickened walls or vascular cell proliferation, is seen but does not imply an unfavorable prognosis; necrosis and mitoses are uncommon.
• Unlike diffuse fibrillary astrocytomas of any grade, pilocytic astrocytomas have a narrow infiltrative border with the surrounding brain

• Biphasic (cystic and solid) pilocytic astrocytoma with numerous Rosenthal fibers.

• No mutation of infiltrative astrocytoma
• if NF1--> neurofibromin
• BRAF

the hypothalamic region

• Temporal lobe of children and young adults, usually with a history of seizures
• Neoplastic, occasionally bizarre, astrocytes, which are sometimes lipidized; these cells often express neuronal and glial markers. The degree of nuclear atypia can be extreme and may suggest a high-grade astrocytoma, but the presence of abundant reticulin deposits, relative circumscription, and chronic inflammatory cell infiltrates, along with the absence of necrosis and mitotic activity, redirects the pathologist toward the diagnosis
• Necrosis and mitosis--> poorer prognosis

• Grade I-Pilocytic astrocytoma: Benign cytological features
• II-Low-grade astrocytoma: Moderate cellularity-no anaplasia or mitotic activity
• III- Anaplastic astrocytoma: Cellularity, anaplasia, mitoses
• IV-Glioblastoma: Same as Grade III plus microvascular proliferation and necrosis

• brainstem gliomas occur mostly in the first two decades of life and make up about 20% of primary brain tumors in this age group.
• intrinsic pontine gliomas (the most common, with an aggressive course and short survival

• 5% to 15% of gliomas and are most common in the fourth and fifth decades.
• Patients may have had several years of neurologic complaints, often including seizures.
• The lesions are found mostly in the cerebral hemispheres, with a predilection for white matter

• Well-circumscribed, gelatinous, gray masses, often with cysts, focal hemorrhage, and calcification.
• Cells resemble normal oligodendrocytes
• Has a clear halo of cytoplasm 
• The tumor typically contains a delicate network of anastomosing capillaries.
• Calcification
• As the tumor cells infiltrate cerebral cortex, there is often formation of secondary structures, often with tumor cells arrayed around neurons (perineuronal satellitosis). No mitosis

loss of heterozygosity for chromosomes 1p and 19q

• grade III/IV
• increased cell density, nuclear anaplasia, increased mitotic activity, and necrosis
• Also often present in these higher grade lesions are discrete round cells with cytoplasmic GFAP and nuclei that resemble the other elements of the tumor. These microgemistocytes differ from gemistocytic astrocytes in that they lack abundant processes; the intermediate filaments are restricted to a small lump of cytoplasm

• In the first two decades of life they typically occur near the fourth ventricle and constitute 5% to 10% of the primary brain tumors in this age group.
• In adults the spinal cord is the most common location; tumors in this site are particularly frequent in the setting of neurofibromatosis type 2 (NF2).

• Low grade
• Due to proximity to vital structures: not resectable in the fourth ventricle
• Between the nuclei there is a variably dense fibrillary background. Tumor cells may form glandlike round or elongated structures (rosettes, canals) that resemble the embryologic ependymal canal, with long, delicate processes extending into a lumen 
• More frequently present are perivascular pseudorosettes, in which tumor cells are arranged around vessels with an intervening zone consisting of thin ependymal processes directed toward the wall of the vessel.
• GFAP expression is found in most ependymomas

• Occur in the filum terminale of the spinal cord and contain papillary elements in a myxoid background, admixed with ependymoma-like cells.
• Cuboidal cells, sometimes with clear cytoplasm, are arranged around papillary cores containing connective tissue and blood vessels.
• The myxoid areas contain neutral and acidic mucopolysaccharides

• NF2 gene on chromosome 22 is commonly mutated in ependymomas in the spinal cord but not at other sites.
• Supratentorial lesions are more likely to show alterations in chromosome 9

• Posterior fossa ependymomas often manifest with hydrocephalus secondary to progressive obstruction of the fourth ventricle rather than invasion of the pons or medulla.
• Because of the relationship of ependymomas to the ventricular system, CSF dissemination is a common occurrence and portends a poor prognosis.
• Posterior fossa lesions have the worst overall outcome. The clinical outcome for completely resected supratentorial and spinal ependymomas is better.

• slow-growing nodules attached to the ventricular lining and protruding into the ventricle
• clumps of ependymal-appearing nuclei scattered in a dense, fine, glial fibrillar background

• Most common in children, in whom they are usually found in the lateral ventricles.
• In adults, they more often involve the fourth ventricle. These markedly papillary growths almost exactly recapitulate the structure of the normal choroid plexus.
• The papillae have connective tissue stalks covered with a cuboidal or columnar epithelium.
• Clinically, choroid plexus papillomas usually present with hydrocephalus due to obstruction of the ventricular system by tumor or to overproduction of CSF

• Young adults.
• The cyst is attached to the roof of the third ventricle, where it can obstruct one or both of the foramina of Monro and, as a result, causes noncommunicating hydrocephalus, which may be rapidly fatal.
• Headache, sometimes positional, is an important clinical symptom.
• The cyst has a thin, fibrous capsule and a lining of low to flat cuboidal epithelium; it contains gelatinous, proteinaceous material

ganglioglioma

• Most often present with seizure
• Temporal lobe and often have a cystic component. The neoplastic ganglion cells are irregularly clustered and have apparently random orientation of neurites. Binucleate forms are frequent. The glial component of these lesions usually resembles a low-grade astrocytoma, lacking mitotic activity and necrosis

• lowgrade tumor of childhood that often presents as a seizure disorder
• MC superficial temporal
• attenuation of the overlying skull,
• Multiple discrete intracortical nodules of small, round cells, arranged in columns around central cores of processes, and are associated with a myxoid background, known as the “specific glioneuronal element.” There are well-differentiated “floating neurons” that sit in the pools of mucopolysaccharide-rich fluid of the myxoid background.
• The larger neurons and the small, round cells of the specific element express neuronal markers. Surrounding the nodules, there may be focal cortical dysplasia and sometimes low-grade astrocytoma.

Medulloblastoma

• Children
• Cerebellum

Medulloblastoma

• In children, medulloblastomas are located in the midline of the cerebellum, but lateral locations are more often found in adults. Rapid growth may occlude the flow of CSF, leading to hydrocephalus.
• The tumor is often well circumscribed, gray, and friable, and may be seen extending to the surface of the cerebellar folia and involving the leptomeninges 
• On microscopic examination medulloblastoma is extremely cellular, with sheets of anaplastic cells 
• Individual tumor cells are small, with scant cytoplasm and hyperchromatic nuclei that are frequently elongated or crescent shaped. Mitoses are abundant, and markers of cellular proliferation, such as Ki-67, are detected in a high percentage of the cells.
• The tumor may express neuronal (neurosecretory granules or Homer Wright rosettes, as occur in neuroblastoma; ) and glial (GFAP+) phenotypes.
• The desmoplastic variant is characterized by areas of stromal response, marked by collagen and reticulin deposition and nodules of cells forming “pale islands” that have more neuropil and show greater expression of neuronal markers
• At the edges of the main tumor mass, medulloblastoma cells have a propensity to form linear chains of cells infiltrating through cerebellar cortex to aggregate beneath the pia, penetrate the pia, and seed into the subarachnoid space.
• Dissemination through the CSF is a common complication, presenting as nodular masses elsewhere in the CNS, including metastases to the cauda equina that are sometimes termed drop metastases

Medulloblastoma

• MArkers of proliferation as Ki-67.
• The tumor may express neuronal (neurosecretory granules or Homer Wright rosettes, as occur in neuroblastoma ) and glial (GFAP+) phenotypes

Loss of material from 17p, with an abnormal chromosome derived from duplication of this chromosome's long arm (isochromosome 17q or i(17q)).

Increased levels of neurotrophin receptor TRKC and nuclear accumulation of β-catenin--> better prognosis

• Loss of 17p--> poor
• MYC amplification--> worst

• Wnt--> Turcot
• SHH--> Gorlin

Radiosensitivity

• Highly malignant
• children
• presence of rhabdoid cells, resembling those of a rhabdomyosarcoma
• eosinophilic cytoplasm, sharp cell borders and eccentrically located nuclei
• The cytoplasm of the rhabdoid cell contains intermediate filaments and is immunoreactive for epithelial membrane antigen and vimentin
• Negative for myoglobin and desmin
• Chromosome 22  alteration

Primary CNS lymphoma

• Primary brain lymphoma is often multifocal within the brain parenchyma, yet nodal, bone marrow, or extra-nodal involvement outside of the CNS is a rare and late complication.
• Conversely, lymphoma arising outside the CNS rarely involves the brain parenchyma; involvement of the nervous system, when it occurs in lymphoma, is usually manifested by the presence of malignant cells within the CSF and around intradural nerve roots, and occasionally by the infiltration of superficial areas of the cerebrum or spinal cord by malignant cells
• Most primary brain lymphomas are of B-cell origin.
• In the setting of immunosuppression, the cells in nearly all such tumors are latently infected by Epstein-Barr virus.
• Overall, primary lymphomas of the CNS are aggressive, with relatively poor response to chemotherapy compared with peripheral lymphomas

infected with EBV

• Primary---> parenchymal
• Secondary--> never parenchymal

• Multiple
• Periventricular and perivascular spread
• extensive areas of central necrosis
• Diffuse large-cell B-cell lymphomas are the most common histologic group
• Reticulin stains demonstrate that the infiltrating cells are separated from one another by silver-staining material; this pattern, referred to as “hooping,” is characteristic of primary brain lymphoma
• In addition to expressing B-cell markers, most of the cells also express BCL-6

Reticulin stains demonstrate that the infiltrating cells are separated from one another by silver-staining material; this pattern, referred to as “hooping,” is characteristic of primary brain lymphoma

• Along the midline, most commonly in the pineal and the suprasellar regions
• 10% in Japanese people 
•  first two decades
• Teratoma mc
• If in the pineal M>>>>F
• In contrast to lymphomas, however, metastasis of a gonadal germ cell tumor to the CNS is not uncommon
• Germinoma in CNS=Seminoma of the testis
• CSF levels of tumor markers including α-fetoprotein and β-human chorionic gonadotropin can be used to aid in diagnosis

1) Arise from specialized cells of the pineal gland (pineocytes) that have features of neuronal differentiation.

• 2) High-grade pineal tumors tend to affect children, while lower-grade lesions are found more often in adults.
• The highly aggressive pineoblastoma commonly spreads throughout the CSF space. It occurs with increased frequency in individuals with germline mutations in RB (so-called trilateral retinoblastoma).

• 1) Meningiomas are predominantly benign tumors of adults, usually attached to the dura, that arise from the meningothelial cell of the arachnoid
• 2) NF-2, history of radiation

meningothelial cells of arachnoid

• Rounded masses with well-defined dural bases that compress underlying brain but are easily separated from it.
• Extension into the overlying bone may be present.
• The surface of the mass is usually encapsulated.
• They may also grow en plaque, in which the tumor spreads in a sheetlike fashion along the surface of the dura. This form is commonly associated with hyperostotic reactive changes in the overlying bone. Gross evidence of necrosis or extensive hemorrhage is not present
• Psammoma bodies

False

• Syncytial (“meningothelial”), appropriately named for the whorled clusters of cells that sit in tight groups without visible cell membranes
• Fibroblastic, with elongated cells and abundant collagen deposition between them
• Transitional, which share features of the syncytial and fibroblastic types
• Psammomatous, with psammoma bodies, apparently formed from calcification of the syncytial nests of meningothelial cells
• Secretory, with PAS-positive intracytoplasmic droplets and intracellular lumens by electron microscopy;
• Microcystic, with a loose, spongy appearance.

• Xanthomatous degeneration, metaplasia (often osseous), and moderate nuclear pleomorphism are common in meningiomas.
• Among these lesions, proliferation index has been shown to be a predictor of biologic behavior

• (WHO grade II/IV) are lesions with a higher rate of recurrence and more aggressive local growth, and may require radiation therapy in addition to surgery.
• They are distinguished from lower grade meningiomas by the presence of either a mitotic index of four or more mitoses per 10 high power fields or at least three atypical features (increased cellularity, small cells with a high nuclear-to-cytoplasmic ratio, prominent nucleoli, patternless growth, or necrosis).
• Certain histologic patterns (clear cell and chordoid) are also considered to be grade II/IV because of their more aggressive behavior

• (WHO grade III/IV) is a highly aggressive tumor with the appearance of a high-grade sarcoma, but retaining some histologic evidence of meningothelial origin.
• Mitotic rates are often extremely high (>20 mitoses per 10 high power fields). 
• Papillary meningioma (with pleomorphic cells arranged around fibrovascular cores) and rhabdoid meningioma (with sheets of tumor cells with hyaline eosinophilic cytoplasm containing intermediate filaments) both have such a high propensity to recur that they are also considered to be WHO grade III/IV tumors

epithelial membrane antigen

Keratin and CEA

The most common cytogenetic abnormality is loss of chromosome 22, especially the long arm (22q) containing NF2

Common sites of involvement include the parasagittal aspect of the brain convexity, dura over the lateral convexity, wing of the sphenoid, olfactory groove, sella turcica, and foramen magnum

present at multiple sites, especially in association with acoustic neuromas or glial tumors

Meningiomas often express progesterone receptors and may grow more rapidly during pregnancy

Meningioma: whorl patern