Cns Tumors

CNS Tumors Jeffrey W. Oliver, M.D.

Learning Objectives • Outline the various families of primary brain tumors described in class. • List morphologic features used to grade fibrillary astrocytomas. • Describe the typical clinical course of the three grades of fibrillary astrocytoma, and compare to that of JPA, PXA, and SEGA.

Learning Objectives • Describe the clinical and morphologic features of JPA, PXA, and SEGA. • Compare and contrast treatment and prognosis of oligodendroglioma vs. fibrillary astrocytomas. • Name the molecular/cytogenetic abnormalities of oligodendroglioma and how they affect prognosis.

Learning Objectives • Explain the clinical and morphologic features of ependymal tumors including the subtypes myxopapillary ependymoma, subependymoma, choroid plexus papilloma, and colloid cyst of 3rd ventricle. • Describe two pathophysiologic mechanisms by which choroid plexus papilloma can cause hydrocephalus.

Learning Objectives • List immunophenotypic markers of gliomas, neuronal tumors, meningiomas, and Schwann cells. • Explain the nomenclature of primitive neuroectodermal tumors. • Recognize the morphologic features of medulloblastoma.

Learning Objectives • Describe clinical and morphologic features of primary CNS lymphoma. • Recognize morphologic features of meningioma, and list subtypes which are more likely to recur. • Name the most common locations of primary CNS germ cell tumors.

Learning Objectives • List the five malignant tumors most likely to metastasize to the CNS. • Recognize morphologic features of schwannoma. • Explain the clinical features and molecular pathogenesis (where discussed in class) of each of the following phacomatoses: neurofibromatosis types I and II, tuberous sclerosis, and Von HippelLindau syndrome.

CNS Tumors • About half primary, half metastatic • In children, most are infratentorial, in adults most are supratentorial • Limitations in resectability • Benign-appearing tumors can infiltrate surrounding structures and be lethal • Even most malignant primary CNS tumors rarely metastasize outside the CNS • Meningeal spread common

Gliomas • • • •

Astrocytomas Oligodendrogliomas Ependymomas All usually at least partially positive for the glial antigen glial acid fibrillary protein (GFAP)

Fibrillary Astrocytoma • Can occur in children or adults, but more common in adults • Symptoms include HA, seizures, or focal neurologic signs depending on location of tumor

Fibrillary Astrocytoma • Several grading schemes exist, but easiest is three-tiered system: • Grade I = low grade fibrillary astrocytoma • Grade II = anaplastic astrocytoma • Grade III = glioblastoma multiforme (GBM)

Fibrillary Astrocytoma • Low grade lesions are infiltrative and destructive, but indolent; mean survival > 5 years; tendency to evolve to higher grade over time • GBM is very aggressive despite all forms of therapy, death usually in 8-10 months • Gliomatosis cerebri: multiple regions or entire brain affected

Fibrillary Astrocytoma • Can be very small to huge, and can occur anywhere within the CNS • Low grade lesions blend almost imperceptibly into surrounding brain tissue, are more cellular than normal brain or gliosis, have fibrillary GFAP-positive background, and variable amount of nuclear pleomorphism/atypia

Anaplastic Astrocytoma • More cellular and more atypical than lowgrade lesions • Mitotic figures are present • When brightly eosinophilic cells predominate, called gemistocytic astrocytoma, usually qualifies as anaplastic astrocytoma

Glioblastoma Multiforme • Pleomorphic gross appearance with areas of hemorrhage and necrosis; often crosses midline through white matter tracts “butterfly lesions”; ring enhancing • More cellular and mitotically active than anaplastic astrocytoma, but real defining features are necrosis (sometimes with peripheral pseudopalisading) and vascular (endothelial) proliferation

“Benign” Astrocytomas • Juvenile pilocytic astrocytoma (JPA), pleomorphic xanthoastrocytoma (PXA), and subependymal giant cell astrocytoma (SEGA) • More common in children than adults • Usually benign, but rarely can transform into more aggressive lesions

Juvenile Pilocytic Astrocytoma • Can occur anywhere in CNS, but cerebellum is most common • Often cystic with mural nodule • Bipolar cells with long GFAP-positive processes, increased number of vessels (but not endothelial proliferation), Rosenthal fibers (large red extracellular cigar-shaped bodies)

Pleomorphic Xanthoastrocytoma • Almost always superficial temporal lobe in children to young adults with history of seizures • Very atypical astrocytes and foamy cells • Rosenthal fibers or eosinophilic granular bodies (smaller red extracellular globules, probably early Rosenthal fibers)

Subependymal Giant Cell Astrocytoma • Very strong association with tuberous sclerosis • Tubers (cerebral hamartomas) probably evolve into SEGA • Any subependymal location • Large (but not really giant) epithelioid astrocytes without mitotic activity or necrosis

Oligodendroglioma • Most common in 4th-5th decade, often with a history of seizures • Most common in white matter of cerebral hemispheres • More chemosensitive than astrocytomas, especially if positive for deletions on chromosome 1p and 19q • Average survival = 5-10 years

Oligodendroglioma • Well-circumscribed lesions, often with hemorrhage and calcification • Sheets of cells with uniform round-oval nuclei, perinuclear halos, fine capillary network, calcifications • Usually at least partially GFAP-positive

Ependymoma • Usually arise in periventricular locations, in children most commonly around 4th ventricle; in adults usually spinal cord • Intracranial lesions often give rise to hydrocephalus, disseminate into CSF, and have mean survival of 4 years despite therapy and benign histologic appearance

Ependymoma • More well-circumscribed than fibrillary astrocytomas • Fairly uniform cells with round-oval nuclei and fibrillary background • GFAP-positive fibrillary processes surround vessels “perivascular pseudorosettes” • Sometimes cells form true rosettes

Myxopapillary Ependymoma • Arises at filum terminale • Cuboidal ependymal-like cells arranged around papillary structures within myxoid background • Recurrence likely if incompletely resected

Subependymoma • Solid periventricular tumors that often protrude into ventricles • Benign, and usually asymptomatic, but may cause hydrocephalus if large enough or in strategic location • Clusters of small ependymal-like cells scattered in a fibrillary background

Choroid Plexus Papilloma • Most common in children (usually in lateral ventricles), but also occur in adults (usually in 4th ventricle) • Look like exaggerated normal choroid plexus • Two mechanisms for making hydrocephalus: ventricular obstruction & CSF overproduction • Choroid plexus carcinoma = malignant version, also more common in children; looks like any other adenocarcinoma, so difficult to differentiate from metastatic lesion

Colloid Cyst of Third Ventricle • Cystic lesion containing gelatinous material that hangs from roof of 3rd ventricle • Most common in young adults • Hydrocephalus, which often presents as positional HA

Neuronal Tumors • • • •

Gangliocytoma Ganglioglioma Central Neurocytoma Dysembryoplastic neuroepithelial tumor (DNET) • Positive for neural antigens synaptophysin and neurofilament

Gangliocytoma • • • •

Slow growing, usually benign Most common in children Well-circumscribed, often calcified Clumps of large neurons “ganglion cells” in relatively acellular stroma

Ganglioglioma • Similar to gangliocytoma, but also has astrocytic component • Usually slow growing, but glial component sometimes transforms to high grade lesion with poor prognosis

Central Neurocytoma • Usually intraventricular near the foramen of Munro • Young to middle-age adults most common • Mimics oligodendroglioma: sheets of uniform cells with perinuclear halos, but positive for neuronal markers and GFAP-negative • Prognosis is excellent, especially if completely excised

Dysembryoplastic Neuroepithelial Tumor • A multinodular lesion, usually of temporal lobe, in children with history of seizures • Often microcystic with neurons “floating” in pools of myxoid material and surrounding glial cells without atypia • Good prognosis with complete excision

Primitive Neuroectodermal Tumors • • • • • •

Cerebellum – Medulloblastoma Cerebral Cortex – Central Neuroblastoma Pineal – Pineoblastoma Adrenal Medulla – Neuroblastoma Retina – Retinoblastoma Elsewhere - PNET

Medulloblastoma • Usually in children, exclusively in cerebellum • Often associated with loss of material from chromosome 17p; usually in the form of i(17q) • Untreated prognosis dismal, but with good excision and radiation 5 year survival about 75%

Medulloblastoma • Usually in midline of cerebellum (but often lateral cerebellum in adults) • Very cellular with little cytoplasm, hyperchromatic nuclei, high mitotic rate; can express neuronal and/or glial markers; Homer Wright rosettes • Propensity for CSF seeding with “drop” metastases

Primary CNS Lymphoma • The most common CNS tumor in immunosuppressed patients, but can also occur in immunocompetent patients (mean age of 60) • Primary = originally arising in CNS, as opposed to metastatic spread of lymphoma from a distant primary site (which is rare)

Primary CNS Lymphoma • Usually high-grade B cell lymphoma with very aggressive behavior and poor response to chemotherapy • In immunosuppressed patients, EBV genome usually present in the tumor cells

Primary CNS Lymphoma • Often multifocal, usually fairly wellcircumscribed, often with central necrosis, periventricular spread common • Tumor cells accumulate around vessels

CNS Germ Cell Tumors • Usually in midline: pineal or suprasellar area • Most common in adolescents and young adults • Must be differentiated from metastasis • Histologic types and responses to treatment parallel those seen in gonads, but CSF spread may complicate treatment

Pineocytoma • Well-differentiated neuronal tumor arising from pineocytes. No necrosis or mitotic activity • As opposed to pineoblastoma, which resembles medulloblastoma: small cells with little cytoplasm, high mitotic rate, necrosis

Meningioma • Usually benign tumors arising from meningothelial cells of arachnoid, usually attached to dura, but can be intraventricular • Usually seen in adults • F:M = 2:1, but 10:1 in spinal meningiomas • Cells express progesterone receptors and may grow rapidly during pregnancy • Increased risk, and often multiple, in patients with neurofibromatosis type II

Meningioma • Rounded dural-based lesions that compress underlying brain, but are typically easily separated from it; can present as meningeal plaque; can invade overlying bone • Many histologic variants: syncytial, fibroblastic, transitional, secretory, psammomatous • Usually positive for epithelial membrane antigen (EMA)

Meningioma • Papillary and clear cell variants have poorer prognosis, more likely to recur • Malignant meningioma is rare, and primarily defined by invasion into underlying brain tissue, usually also with mitotic activity, nuclear atypia, and necrosis

Metastatic Tumors • Account for about half of all intracranial tumors • 5 most common primaries: lung, breast, melanoma, kidney, GI tract • Often multiple, and can involve meninges • Usually sharply circumscribed, often at gray-white junction

Peripheral Nerve Sheath Tumors • Schwannoma (Neurilemmoma) • Neurofibroma • Malignant Peripheral Nerve Sheath Tumor (MPNST) • These can arise within millimeters of the transition from oligodendroglial to Schwann cell myelinization, and so can be intracranial • Positive for Schwann cell marker S-100 protein

Schwannoma • Benign tumors arising from Schwann cells • Symptoms are usually those of nerve compression • Sporadic, or associated with neurofibromatosis type II

Schwannoma • If extradural, often arise from large peripheral nerve trunks • Intracranial lesions most commonly arise at cerebellopontine angle, attached to CN VIII, and present with tinnitus or hearing loss “acoustic neuroma”

Schwannoma • Encapsulated, usually attached to the nerve, but usually can be separated from it • Mixture of two growth patterns: relatively cellular Antoni A areas with palisading nuclei “Verocay bodies”, and Antoni B areas of less dense cellularity in myxoid stroma • Degenerative changes, esp. nuclear atypia in “ancient schwannomas”

Solitary/Cutaneous Neurofibroma • Small benign nodules in skin, subcutaneous fat, or peripheral nerve • Spindle cells in fibrotic stroma • Can be associated with neurofibromatosis type I

Plexiform Neurofibroma • Almost always associated with neurofibromatosis type I • Significant risk of malignant transformation • Usually arise at large nerve trunks, commonly multiple • Spindle cells in a myxoid stroma closely infiltrate between nerve fibers; cannot be separated from the nerve

Malignant Peripheral Nerve Sheath Tumor • Invasive, malignant tumor arising from nerve trunks; multiple recurrences are usually followed by metastatic disease • Arise de novo or from malignant transformation of plexiform neurofibromas • Strongly associated with neurofibromatosis type I and history of radiation exposure

Malignant Peripheral Nerve Sheath Tumor • Primarily spindle cells with nuclear atypia, high mitotic rate, necrosis • May have mixture of sarcomatous elements, or be epithelioid

Neurocutaneous Syndromes (Phakomatoses) • Inherited diseases with combination of hamartomas or neoplasms of skin and nervous system • Neurofibromatosis types I & II • Tuberous Sclerosis • Von Hippel-Lindau disease

Neurofibromatosis type I (von Recklinghausen Disease) • AD disorder with multiple plexiform and cutaneous neurofibromas, optic nerve gliomas, pigmented nodules of the iris “Lisch nodules,” hyperpigmented macules “café au lait spots” • Due to mutations in tumor suppressor gene NF1 on chromosome 17, which codes for neurofibromin

Neurofibromatosis type II • AD disease, less common than type I, with bilateral acoustic neuromas and multiple meningiomas, sometimes glial hamartomas • Mutations in NF2 gene on chromosome 22, which codes for the protein merlin (a cytoskeletal protein)

Tuberous Sclerosis • AD disease with cortical hamartomas “tubers” which can evolve to SEGA, renal angiomyolipoma, various organ cysts, subungual fibromas, skin lesions: angiofibromas, leathery thickening “shagreen patch,” hypopigmented areas “ash-leaf patches”

Tubers • Firm areas with haphazardly arranged neurons and large eosinophilic cells which express both neuronal and glial antigens • Subependymal lesions may bulge into ventricles “candle guttering”; may evolve into SEGA

Von Hippel-Lindau Disease • AD disease with hemangioblastomas of cerebellum & retina, various organ cysts, and greatly increased risk of renal cell carcinoma • Mutations of a tumor suppressor gene on chromosome 3, which codes for pVHL; pVHL inhibits the elongation phase of RNA synthesis

Hemangioblastoma • Benign tumors, typically present as a cyst with a mural nodule • Very vascular with capillary-sized or slightly larger vessels, interstitial cells with lipid-rich vacuolated cytoplasm • Can mimic metastatic renal cell carcinoma • 10% have polycythemia due to ectopic erythropoietin production