TUMORS of nervous system
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1 TUMORS of nervous system By: Shifaa Alqa qa Done By : Ola Hijjawi
2 CNS tumors : The annual incidence of CNS tumors ranges from 10 to 17 per 100,000 persons for intracranial tumors and 1 to 2 per 100,000 persons for intraspinal tumors. According to CNS tumors, CNS tumors can be classified to: 1) primary tumors----- about half to three quarters Of CNS tumors 2) Metastatic tumors or Secondary tumors ---- one fourth to one half of intracranial tumors
3 CNS tumors make 20% of all childhood tumors make up a larger proportion of childhood cancers (20% of all pediatric tumors) Childhood CNS tumors differ from those in adults in both histologic subtype and location Childhood ---- posterior fossa tumors Adults ---- supratentorial tumors
4 Tumors of the nervous system have unique characteristics that set them apart from neoplastic processes elsewhere in the body: - No premalignant or in situ stages Remember in carcinomas there are stages but in CNS tumors No - Even low-grade lesions may infiltrate large regions of the brain --- serious clinical deficits In CNS tumors we don t focus on grade too much, but we focus : 1) location of tumor 2)Burden of it - The anatomic site of the neoplasm can influence outcome independent of histologic classification due to local effects - Even the most highly malignant gliomas rarely spread outside of the CNS; in addition to local infiltration, the subarachnoid space allows for spread to distant sites along the neuroaxis. There is NO mets of brain tumors to other sites of the body cuz : 1) No lymph in brain 2) Brain tissue cannot survive outside the brain 3) Thick meninges It might happen rarely in one way only : by Subaracinoid space into CSF
5 Most common type of primary CNS tumors Gliomas Glioma means : Tumors in neuroglial cells : oligodedrocytes, astrocytes, ependymal cells astrocytomas, oligodendrogliomas, All of them are malignant although they end in oma Ependymomas solid masses
6 Astrocytoma Most common type of glioma, composed of malignant astrocytes Classified into : Diffuse astrocytomas Tumor make infiltration and invasion on normal brain tissue Pilocytic astrocytomas Low grade tumor, well defined mass not infiltrated
7 Diffuse Astrocytoma account for about 80% of adult gliomas most frequent in the fourth through the sixth decades of life usually are found in the cerebral hemispheres Symptoms : (Mass effects) : seizures, headaches, and focal neurologic deficits related to the anatomic site of involvement & size of tumor
8 WHO classification of tumors : from grade (1 to 4 ) grade 1 : low grade Diffuse astrocytoma 3 types: Well-differentiated astrocytoma (grade II/IV), Anaplastic astrocytoma (grade III/IV), Glioblastoma (grade IV/IV), in the past it s name was glioblastoma multiform with increasingly grim prognosis as the grade increases. Grading tumor depend on : 1) Cell density of tumor 2) Mitosis 3) Presence or absence of necrosis ( if necrosis happened we call it glioblastoma ( highest grade)
9 Diffuse astrocytoma problem is that even if it was low grade (2/4) it has rapid progression after few years Well-differentiated astrocytomas can be static for several years, but at some point they progress; the mean survival is more than 5 years. Eventually, patients suffer rapid clinical deterioration that is correlated with the appearance of anaplastic features and more rapid tumor growth. Other patients present with glioblastoma Highest grade (4/4) from the start. Once the histologic features of glioblastoma appear, the prognosis is very poor; with treatment (resection, radiotherapy, and chemotherapy), the median survival is only 15 months.
10 variety of acquired mutations cause the brain tumors: - glioblastoma: Most common one : *loss-of-function mutations in the p53 and Rb tumor suppressor genes *gain-of-function mutations in PI3K pathways (it has onco genes) - lower-grade astrocytomas: IDH1 and IDH2 mutations (isocitrate dehydrogenase enzyme) Mainly we use IDH1, Presence of IDH1 mutations give good prognosis High grade tumors have : P53 & Rb mutations
11 - MORPHOLOGY: poorly defined, infiltrative (No discrete mass) --- Infiltration beyond the grossly evident When we take histological section we see that tumor is presence in bigger spaces and areas than on gross evident Gray, firm, soft/gelatinous, cystic, hemorrhage Glioblastoma---- It has Hemorrhage and necrosis and whitish and grey areas variation in the gross appearance of the tumor from region to region - microscopic: +Cellularity than normal brain Pleomorphism Fibrillary background m.imp cuz it have astrocyte which have cytoplasmic extension which give it the fibillary appearance Mitotic figures MITOTIC INDEX : WE Count 100 Cell And See How Much Mitosis In The we take the Mean mitotic index EX: FROM 0-5 mitosis : GRADE 2 / 5-10 mitosis : GRADE 3 / MORE THAN 10 : GRADE 4 necrosis (often with pseudopalisading nuclei) necrosis surrounded by cell nuclei vascular proliferation
12 GFAP : Immunohistochemical stain ( to confirm the diagnose ) glial fibrillary acidic protein (GFAP)-positive astrocytic cell processes
13 Pilocytic Astrocytoma Relatively benign tumors, Typically affecting children and young adults Most commonly located in the cerebellum Tumors that involve the hypothalamus are especially problematic because they cannot be resected completely. Pilocytic tumor : Low grade tumor, but it cause problem if it happen at vital site as hypothalamus ( it will affect prognosis )
14 A high proportion of pilocytic astrocytomas have activating mutations in the serinethreonine kinase BRAF
15 - MORPHOLOGY: Most imp thing : cystic, with a mural nodule in the wall of the cyst (in the solid component of tumor), it is usually well circumscribed - Microscopic: What helps us in classifying tumors : Radiologic examination : MRI, CT scan Astrocytes in this tumor are Bipolar cells ( not too much extensions) Rosenthal fibers, at any area with gliosis Eosinophilic granular bodies Microcysts Necrosis and mitoses are rare GFAP-positive Most imp things that distinguish this tumor are: Cystic with mural nodule Rosenthal fibers
16 symptomatic recurrence from incompletely resected lesions is often associated with cyst enlargement, rather than growth of the solid component So the prognosis depend mainly on the complete surgical excision of tumor
17 Oligodendroglioma 5% to 15% of gliomas most commonly are detected in the fourth and fifth decades of life. found mostly in the cerebral hemispheres, mainly in the frontal or temporal lobes better prognosis than that for patients with astrocytomas of similar grade Better prognosis than diffuse astrocytoma Have grade 2,3,4 No grade 1
18 Treatment with surgery, chemotherapy, and radiotherapy yields an average survival of 10 to 20 years for well-differentiated (WHO grade II) or 5 to 10 years for anaplastic (WHO grade III) oligodendrogliomas In comparison with Diffuse astrocytoma grade 2 has 5 years survival rate Grade 4 has years maximum
19 Mutation signature of this tumor : short arm of ch1p & long arm of ch19q ( they occur together ) Presence of this deletion give it better prognosis The most common genetic findings are deletions of chromosomes 1p and 19q, alterations that typically occur together. Tumors with deletions of 1p and 19q are usually highly responsive to chemotherapy and radiotherapy.
20 MORPHOLOGY: Infiltrative, Gelatinous, cysts, hemorrhage, calcification (m.imp) Malignant oligodendrocyte ( fried egg appearance nucleus surrounded by space ) Microscopic: Delicate network of anastomosing capillaries Calcification, present in as many as 90% of cases cell density high, nuclear anaplasia and mitotic activity for grading (High grade have necrosis)
21 Ependymoma In Children in ventricular system but in adult in Spinal Cord Most often arise next to the ependymalined ventricular system the first 2 decades of life--- near the fourth ventricle, 5% to 10% of the primary brain tumors in this age group Adults---- spinal cord, neurofibromatosis type 2 ( in adults associated with neurofibromatosis type 2 syndrome )
22 The clinical outcome for completely resected supratentorial and spinal ependymomas is better than for those in the posterior fossa Prognosis depend on anatomical location of tumor
23 MORPHOLOGY: rosettes, canals perivascular pseudorosettes Normal ependymal cells make tubes are called rosettes In tumors they try to resemble the normal cells, so they make aggregation of cells around fibillary background this is also called rosettes, canals If the cells aggregate around BV this is called: pseudorosettes Anaplastic ependymomas show increased cell density, high mitotic rates, necrosis, and less evident ependymal differentiation Ependymoma has 2 grades : Grade 2,3 and diff in mitosis, necrosis, cellularity
24 Meningiomas Have 4 Grades benign tumors Arise from arachnoid meningothelial cells ( lining subarachnoid space so this tumor attached to dura ) Adults Meningiomas may be found along any of the external surfaces of the brain as well as within the ventricular system, where they arise from the stromal arachnoid cells of the choroid plexus Diff from glioma that they are extra cranial, glioma are intra cranial
25 Although most meningiomas are easily separable from underlying brain, some tumors infiltrate the brain, a feature that is associated with an increased risk of recurrence. The overall prognosis is determined by: the lesion size and location, surgical accessibility, histologic grade. When infiltration happens the prognosis is bad and the resection is hard
26 Any tumor that is Multiple we think about: familial deposition Multiple---- ( neurofibromatosis type 2 (NF2) in this syndrome there is loss of function mutation in tumor supressor gene Merlin About half of meningiomas not associated with NF2 have acquired loss-of function mutations in the NF2 tumor suppressor gene on the long arm of chromosome 22 (22q). Mutations in NF2 are more common in tumors with certain growth patterns (fibroblastic, transitional, and psammomatous).
27 MORPHOLOGY: well-defined dura-based masses Microscopic diff shapes : Syncytial if cell borders are not clear Fibroblastic if there is fibrosis in background Meningothelial cells looks like plump cells( abundant cytoplasm ) In Meningioma they look like whirls Transitional if both syncytial and fibroblastic patterns Psammomatous if there is calcification/ psammoma spherical areas Secretory if there is secretion of PAS positive material (so we can detect it with PAS stain) This histologic types don t affect prognosis, some types can upgrade the grades like rhabdoid meningioma upgrade the tumor to grade 3
28 WHO grade I/IV Bengin meningioma WHO grade II/IV: - Atypical meningiomas - Prominent nucleoli, increased cellularity, pattern-less growth, higher mitotic rate. - more aggressive local growth and a higher rate of recurrence. WHO grade III/IV: - Anaplastic (malignant) meningiomas : occur once tumor have sacromatoid features - highly aggressive tumors that may resemble a highgrade sarcoma or carcinoma ( Worst prognosis )
29 mostly carcinomas Metastatic Tumors The Brain is common site for: metastatic tumor specially: Carcinoma But remember brain tumors don t mets. The most common primary sites are lung, breast, skin (melanoma), kidney, and gastrointestinal tract
30 Metastases form sharply demarcated masses, often at the gray-white junction, and elicit edema Metastatic tumor come as multiple masses surrounded by edema The boundary between tumor and brain parenchyma is sharp at the microscopic level as well, with surrounding reactive gliosis Reactive gliosis around anything in brain : infection,inflammation,tumor
31 paraneoplastic syndromes may involve the peripheral and central nervous systems Nervous system can be affected by tumors as part of paraneoplastic syndromes Ex: lymbic encephalitis : inflammation in limbic system and brain, it s a result of paraneoplastic syndromes most common in women with ovarian teratoma & has focal neural sign and symptoms so we think about limbic encephalitis.
32 Neuronal Tumors Central neurocytoma Gangliogliomas Dysembryoplastic neuroepithelial tumor
33 Embryonal (Primitive) Neoplasms - Medulloblastoma (Most Important) occurs predominantly in children and exclusively in the cerebellum - primitive neuroectodermal tumors (PNETs)
34 Other Parenchymal Tumors Primary Central Nervous System Lymphoma Germ Cell Tumors Both can arise in the brain
35 Familial Tumor Syndromes This Type caused by Inherited mutations and come with CNS Tumors. Mainly ( Autosomal dominant ) 2 Types : Tuberous sclerosis & von Hippel Lindau Disease: inherited syndromes caused by mutations in various tumor suppressor genes are associated with an increased risk of particular types of cancers
36 Tuberous Sclerosis: - autosomal dominant syndrome - characterized by the development of hamartomas and benign neoplasms involving the brain and other tissues----- cortical tubers and subependymal hamartomas, subependymal giant cell astrocytoma----
37 People with tuberous sclerosis may also have many Benign tumors in diff parts of the body like: renal angiomyolipomas, retinal glial hamartomas, pulmonary lymphangiomyomatosis, cardiac rhabdomyomas. Cysts may be found at various sites, including the liver, kidneys, and pancreas. Cutaneous lesions one of most imp features: include angiofibromas, leathery thickenings in localized patches (shagreen patches), hypopigmented areas (ash leaf patches), and subungual fibromas.
38 Depigmented area in skin
39 Gene Mutations: disruption of either TSC1, which encodes hamartin, or TSC2, which encodes tuberin----- increased mtor---- increases cell growth. The two TSC proteins negatively regulates mtor
40 von Hippel Lindau Disease: - autosomal dominant loss of function mutation on von Hippel Lindau gene on chromosome 3 - Morphology: - Hemangioblastomas--- cerebellum, retina - cysts involving the pancreas, liver, and kidneys and have an increased propensity to develop renal cell carcinoma
41 VHL normally : makes inhibition of HIF1 less angiogenetic factor it regulate the angiogenesis process If loss of function happens the result will be exuberant angiogenesis tumor suppressor VHL, encodes a protein that is part of a ubiquitin-ligase complex that targets the transcription factor hypoxia-inducible factor 1 (HIF) for degradation. lost all VHL protein function these tumors express high levels of HIF, which drives the expression of VEGF, various growth factors, and sometimes erythropoietin, leading to a form of paraneoplastic polycythemia
42 PERIPHERAL NERVE SHEATH TUMORS tumors may manifest as soft tissue masses or with pain or loss of function related to impingement on nerves or other surrounding structures Adults Benign Benign tumors in Schwann cells: Shwannocma If Schwann cells and other cell types like inflammatory cells we call it : neurofibroma Malignant frequent association with the familial tumor syndromes neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2).
43 Schwannomas Well circumscribed & Encapulated separated from the nerves Benign occur in soft tissues, internal organs, or spinal nerve roots The most commonly affected cranial nerve is the vestibular portion of the eighth nerve ( patient with familial schwannoma will have bilateral acoustic schwannoma) ---- hearing loss sporadic, but about 10% are associated with familial neurofibromatosis type 2. The presence of bilateral vestibular schwannomas is a hallmark of NF2
44 Merlin expression is also disrupted in sporadic schwannomas
45 Circumscribed encapsulated masses abutting an adjacent nerve In histology: Antoni A (Hyper cellular area) and Antoni B (Hypo cellular area), Verocay bodies (Hyper cellular area) Axons are largely excluded from the tumor Staining the nerve fiber will give (-) result
46 Neurofibromatosis Type 2 loss of function mutation of the merlin gene (tumor suppressor facilitating E-cadherin mediated contact inhibition) on chromosome 22. multiple schwannomas, meningiomas, ependymomas
47 Neurofibromas Benign Well circumscribed & Not capsulated The nerve fiber inside the tumor cell, so if we stained the nerve fiber in neurofibroma it will be (+) 3 types: Localized cutaneous neurofibromas--- circumscribed, sporadic or NF1 Plexiform neurofibromas NF1, malignant transformation This is the type that comes with neurofibromatosis Diffuse neurofibromas ---- infiltrative, NF1
48 not encapsulated Schwann cells in neurofibroma are admixed with other cell types, including mast cells, fibroblast-like cells and perineurial like cells.
49 Malignant Peripheral Nerve Sheath Tumors They may arise from transformation of a neurofibroma, usually of the plexiform type, About one half of such tumors arise in patients with NF1,
50 Neurofibromatosis Type 1 autosomal dominant Mutations in the tumor suppressor neurofibromin (17q)--- Ras hyperactivity Neurofibromin is a negative regulator of the potent oncoprotein Ras neurofibromas of all three main types, Malignant peripheral nerve sheath tumors, optic gliomas, and other glial tumors. Mainly pilocytic astrocytoma Learning disabilities, seizures, skeletal abnormalities, vascular abnormalities with arterial stenoses, pigmented nodules of the iris (Lisch nodules) in eye examination, and pigmented skin lesions (axillary freckling and café au lait spots) in various degrees.
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