Neuro-Oncology



Neuro-Oncology





Central Nervous System Tumors and Neuropathology


I. Introduction



  • Location of CNS Tumors



    • Intracranial



      • Supratentorial


      • Infratentorial


    • Intraspinal



      • Extradural (e.g., epidural metastases, bone tumors)


      • Intradural



        • Intramedullary (e.g., ependymomas, astrocytomas, glioblastomas)


        • Extramedullary (e.g., schwannomas, meningiomas)


  • Seventy percent of tumors in children are found in the posterior fossa (e.g., cerebellar medulloblastomas, cerebellar astrocytomas, and fourth ventricle ependymomas).


  • Seventy percent of tumors in adults are found in the cerebral hemispheres (e.g., astrocytomas, glioblastomas, metastases, meningiomas).


  • Histogenesis of CNS Cells



    • The brain and spinal cord develop from the neural tube.


    • The neural tube is composed of neuroepithelium, which gives rise to all neurons and microglial cells (astrocytes, oligodendrocytes, ependymal cell, and epithelial cells of the choroid plexus).


    • The mesenchyme gives rise to the microglial cells.


  • Abnormal cellular proliferation (neoplasia) results from the following:



    • Loss of tumor suppressor genes



















































































      Examples:


      GENE


      CHROMOSOME


      ASSOCIATED TUMOR



      P53


      17 p13.1


      Glioblastoma



      CDKN2


      9 p21


      Glioblastoma



      RB1


      13 q14


      Retinoblastoma



      NF1


      17 q11.2


      Pilocytic astrocytoma, neurofibroma



      NF2


      22 q12


      Schwannoma/meningioma



      MEN1


      11 q13


      Pituitary adenoma




      11q, 14q, 17p


      Neuroblastoma




      21q


      Choroid plexus carcinoma




      5q, 9q, 11


      Choroid plexus carcinoma




      9p9


      Malignant meningioma




      1p36, 2p, 6q


      Atypical meningioma




      22q, 18, 1p3


      Meningioma




      17p, 6q, 16q


      Medulloblastoma




      9p or 13 q loss


      Anaplastic ependymoma




      22


      Spinal low-grade ependymoma




    • Activation of protooncogenes (which encode for growth factors, growth factor receptors, and regulators of gene expression)























      Examples:


      GENE


      CHROMOSOME


      MECHANISM



      EGFR


      7 p12


      Amplification/rearrangement



      C-myc, N-myc


      8 q24, 2 p23&24


      Amplification



      H-ras, N-ras


      11 p15, 1 p13


      Overexpansion/point mutation



    • Tumors associated with angiogenesis



      • Metastatic tumors


      • Benign brain tumors



        • Craniopharyngioma


        • Meningioma


        • Pituitary adenoma


      • Malignant brain tumors



        • Anaplastic astrocytoma and glioblastoma multiforme


        • Hemangioblastoma


        • Medulloblastoma


        • Pituitary carcinoma


II. Grading Systems for Astrocytic Tumors



  • Kernohan: based on cellularity, mitoses, pleomorphism, vascularity, and necrosis



    • Grade I: increased cellularity


    • Grade II: greater cellularity than grade I plus pleomorphism


    • Grade III: greater cellularity and pleomorphism than grade II plus vascular proliferation


    • Grade IV: all of the above, plus necrosis and pseuodopallisading


  • Three-tiered: also based on cellularity, mitosis, pleomorphism, vascularity, and necrosis



    • Astrocytoma


    • Anaplastic astrocytoma


    • Glioblastoma multiforme (GBM)—necrosis present


  • World Health Organization classification—1993



    • Grade I: pilocytic astrocytoma, subependymal giant cell astrocytoma


    • Grade II: low-grade astrocytoma—hypercellularity, nuclear atypia


    • Grade III: anaplastic astrocytoma—mitosis, endothelial proliferation


    • Grade IV: GBM—necrosis


III. Glial Tumors



  • Pilocytic astrocytoma



    • Epidemiology: mainly children and adolescents. Can be seen in NF.



    • Clinical features: cerebellar lesions produce symptoms secondary to obstruction of cerebrospinal fluid (CSF) flow (hydrocephalus) or cerebellar dysfunction.


    • Location: cerebellum (children)



      • Brainstem, optic nerve, thalamus, hypothalamus (young adults)


    • Radiology: cyst with mural nodule, which enhances on magnetic resonance imaging (MRI)


    • Pathologic findings: Rosenthal fibers (opaque, homogenous, eosinophilic bodies); long, slender “hairlike” cells (hence the name “pilocytic”); eosinophilic granular bodies


    • Treatment: surgically curable if gross resection possible. Also sensitive to chemotherapy (preferred in children) and x-ray therapy.


    • Prognosis: >90% 10-year survival for cerebellar lesions after total resection


  • Subependymal giant-cell astrocytoma



    • Epidemiology: nearly always associated with tuberous sclerosis


    • Clinical features: produces symptoms by obstructing CSF flow at the foramen of Monro


    • Location: wall of lateral ventricle


    • Radiology: intraventricular enhancing mass on MRI


    • Pathology: aiant astrocytes without significant anaplasia


    • Treatment: surgical debulking for obstructive symptoms


    • Prognosis: slow-growing and benign, rare malignant degeneration


  • Pleomorphic xanthoastrocytoma



    • Epidemiology: most common in second decade of life


    • Clinical features: frequently long history of seizures


    • Location: predilection for superficial temporal lobes


    • Radiology: superficial meningocerebral nodule often associated with a cyst


    • Pathologic findings: lipid-laden astrocytes, extreme pleomorphism, cellular atypia, multinucleated giant cells. NO NECROSIS (often mistaken for GBM)


    • Treatment: surgical resection


    • Prognosis: good with resection. Occasional recurrence, rare malignant degeneration


  • Low-grade astrocytoma



    • Epidemiology: 25% to 30% of all cerebral gliomas. Chiefly in young adults ages 30 to 50 years.


    • Clinical features: seizures are more common than functional deficits, which depend on location.


    • Location: most commonly cerebral hemispheres (adults), but may also occur in the cerebellum, hypothalamus, optic nerve/chiasm, and brainstem (children)


    • Radiology: low density on computed tomography (CT) without enhancement. Low density on T1-weighted and high density on T2-weighted MR images (also without enhancement)


    • Pathologic findings: hypercellular, well-differentiated astrocytes; can be cystic; may be fibrillary (most common) or protoplasmic


    • Treatment: surgical resection with or without x-ray therapy (XRT) for hemispheric lesions


    • Prognosis: median survival, 5 to 6 years with treatment


  • Anaplastic astrocytoma



    • Epidemiology: chiefly in adults ages 30 to 50 years (as with low-grade astrocytoma)


    • Clinical features: sepends on location


    • Location: most commonly cerebral hemispheres (adults), but may occur in the cerebellum, hypothalamus, optic nerve/chiasm, and brainstem (children)



    • Radiology: enhancement usually present, but is of variable degree


    • Pathologic findings: endothelial proliferation, mitosis, nuclear atypia, hyperchromatic nuclei



      • No necrosis. Gemistocytic subtype frequently (80%) transforms into GBM.


    • Treatment: surgical resection, XRT, chemotherapy


    • Prognosis: 50% 2-year survival rate. Frequent transformation into GBM



      • Mean survival is 18 to 36 months.


  • GBM



    • Epidemiology: peak age 45 to 55 years. Male to female ratio is 2:1. Comprises 20% of all intracranial tumors, 50% to 55% of all cerebral gliomas


    • Clinical features: focal neurologic deficits common and depend on location


    • Location: predominantly cerebral hemispheres (particularly frontal and temporal lobes), but may also occur in brainstem, cerebellum, and spinal cord


    • Radiology: ringlike/annular enhancement around central necrosis on CT and MRI with vasogenic edema. Frequently tracks along white matter pathways. When it tracks along the corpus callosum into other hemisphere, this is known as “butterfly” GBM.


    • Pathologic findings



      • Gross: poorly demarcated variegated lesion with areas of necrosis and hemorrhage


      • Micro: pseudopallisading around areas of necrosis and endothelial proliferation are hallmarks. May look “glomeruloid” because it makes its own blood supply


    • Treatment: surgical debulking, XRT, chemotherapy


    • Prognosis: poor, mean 95% mortality in 2 years even with treatment. Age is the most important prognostic indicator, with worse survival in older persons.


  • Oligodendroglioma



    • Epidemiology: ages 30 to 50 years. Comprise 5% of intracranial gliomas


    • Clinical features: frequently long history of seizures


    • Location: cerebral hemispheres (frontal and temporal lobes most common)


    • Radiology: calcification in 50% to 90%; minimal edema and enhancement (may have wispy “chicken wire” enhancement)


    • Pathologic findings



      • Gross: tracks along white matter


      • Micro: “fried-egg” cells (artifact of fixation), delicate vessels (most common primary tumor to bleed) and calcification, geometric patterns, round nuclei with stippled chromatin



        • Variants



          • “Intraventricular oligo”—really a neuronal cell tumor and should be called a central neurocytoma (see section VI, “Neuronal Cell Tumors”).


          • Mixed oligoastrocytoma—oligodendroglial and astrocytic components both occur in significant or roughly equal amounts.


          • Anaplastic oligodendroglioma—increased mitotic rate and pleomorphism. May transform into GBM. Responds to chemotherapy.


    • Treatment: surgical resection and chemotherapy (usually good response to chemotherapy)


    • Prognosis: median survival 5 years


  • Ependymoma



    • Epidemiology: most frequent in childhood and adolescence, peak age 10 to 15 years



      • Comprise 6% of intracranial gliomas, 60% of spinal cord gliomas


      • Most common spinal cord glioma



    • Clinical features: symptoms secondary to obstruction of CSF flow


    • Location: infratentorial in 60% of cases, supratentorial in 40%. Most frequently in region of fourth ventricle; also common in the lumbosacral spinal cord and filum terminale


    • Radiology: intraventricular mass with contrast enhancement and frequent calcification. Obstructive hydrocephalus may be seen.


    • Pathologic findings



      • Gross: well circumscribed, grow by local extension, and may spread in the CSF pathways


      • Micro: ependymal tubules, perivascular pseudorosettes



        • Variant



          • Subependymoma—intraventricular, benign, also causes symptoms from obstruction of CSF flow


    • Treatment: surgical resection followed by XRT with or without full spinal axis radiation


    • Prognosis: 87% 5-year survival rate after resection


  • Gliomatosis cerebri



    • Epidemiology: peak incidence in first and second decades of age; range 6 to 60 years of age


    • Clinical features: impairment of intellect, headache, seizures, and papilledema are common.


    • Location: diffusely infiltrating without discrete tumor mass. Arises deep (in thalamus and basal ganglia) and grows along scaffolding of normal brain.


    • Radiology: homogeneous, hypodensities, loss of grey-white junction, swollen hemispheres on CT. Diffuse increase in T2 signal on MRI. Enhances minimally if at all.


    • Pathologic findings



      • Gross: diffusely enlarged brain.


      • Micro: extensive grey and white matter infiltration by undifferentiated cells with foci of neoplastic astrocytes. Generally falls into the anaplastic astrocytoma subcategory.


    • Treatment: none proven effective


    • Prognosis: poor; survival is months to years.


IV. Primitive Neuroectodermal Tumors (PNET)

“Small blue cell tumors” resembling germinal matrix. Identified by the suffix “blastoma,” with the exception of GBM.



  • Medulloblastoma



    • Epidemiology: most common PNET. Occurs in first decade of life with a second peak in the 20- to 30-year age category. Accounts for about one third of all pediatric posterior fossa tumors.


    • Clinical features: present with cerebellar dysfunction and symptoms secondary to obstruction of CSF flow


    • Location: predilection for midline cerebellum (inferior vermis). Tends to infiltrate the cerebellar hemispheres and spread within the neuraxis via CSF pathways (“drop metastases”).


    • Radiology: contrast-enhancing, rare calcification


    • Pathology: Homer-Wright rosettes (sheets of cells forming rosettes around a central area filled with neuritic processes). These can be seen in any PNET.



      • Variants



        • Desmoplastic—abundant reticulin, more lateral in the cerebellar hemispheres, older children, better prognosis


        • Medullomyoblastoma—very rare, contains immature muscle cells, very malignant



    • Treatment: surgical resection followed by craniospinal XRT (sensitive) with or without chemotherapy


    • Prognosis: >50% 5-year survival rate with treatment. Recurrence, CSF seeding, and distant metastases are not uncommon.


  • Retinoblastoma



    • Epidemiology: children <3 years of age. Is the most common potentially fatal intraocular neoplasm of childhood. Sporadic (60%) or autosomal dominant (40%). Hereditary form tends to be bilateral with early onset. Increased incidence with chromosome 13 deletion (deletion of Rb supressor gene).


    • Clinical features: presenting symptoms include leukocoria (white pupil), squint (strabismus), red and painful eye, and secondary glaucoma.


    • Location: eye, with intracranial extension via optic nerve. Bone marrow is common site of blood-borne mets.



      • “Trilateral tumor” = bilateral retinoblastomas + pineoblastoma


    • Pathologic findings: Homer-Wright rosettes and Flexner-Wintersteiner rosettes (sheets of cells forming rosettes around an empty lumen—recall that Homer-Wright rosettes have neuritic processes filling this central area).


    • Treatment: surgical resection


    • Prognosis: high survival rate (90%) with early treatment


  • Neuroblastoma



    • Epidemiology: first decade of life; two thirds of cases occur before the age of 5 years.


    • Clinical features: can present with myoclonic encephalopathy neuroblastoma syndrome = opsoclonus, myoclonus, and encephalopathy. May be idiopathic or secondary to an occult neuroblastoma.


    • Location: most commonly arises from the sympathetic chain. Cerebral form is uncommon.


    • Radiology: large, discrete, contrast-enhancing lesions with calcification and cysts


    • Pathology: Homer-Wright rosettes, dense sheets of tumor cells. May secrete dopamine and catecholamines, which can be measured in urine (vanilmandelic acid, homovanillic acid). Amplification of N-myc oncogene present in more than one third of cases, and degree of amplification correlates with advanced stage and poor prognosis.


    • Treatment: surgical resection with tumor bed XRT with or without full neuraxis radiation


    • Prognosis: recurrence is frequent.


  • Esthesioblastoma—olfactory neuroblastoma



    • Epidemiology: bimodal age distribution with larger peak in late adulthood


    • Location: olfactory neuroepithelium with involvement of the cribriform plate


    • Radiology: enhancing, dumbbell-shaped mass centered on the cribriform plate


    • Pathologic findings: rare Homer-Wright rosettes, rare olfactory rosettes


    • Treatment: surgical resection


    • Prognosis: favorable with total resection


  • Pineoblastoma

Sep 8, 2016 | Posted by in NEUROLOGY | Comments Off on Neuro-Oncology

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