The Central Nervous System: Tumors The peripheral nervous system Markéta Hermanová Tumor of the CNS nGliomas nChorioid plexus tumors (papillomas and carcinomas) nNeuronal and mixed (glio)neuronal tumors nEmbryonal tumors (poorly differentiated) nPineal tumors nMeningeal tumors nOther primary tumors of CNS nSecondary (metastatic tumors – lung, breast,…) n CNS tumors nClinicopathological features: nCNS tumors do not metastasise to other organs - (only infiltration of adjacent tissues and spreading through - CSF pathways) nLocal effects -Signs related to the site of the tumor -e.g. epilepsy with a temporal lobe tumor, paraplegias in spinal cord tumor nMass effects -Signs and symptoms of space occupying lesions -Vasogenic oedema around CNS tumor -Herniation -Hydrocephalus in posterior fossa tumor Gliomas nAstrocytomas (AC) -Diffuse astrocytomas (grade II) – LG AC (static, with slow progression) nVariants: gemistocytic -Anaplastic astrocytomas (III) -Glioblastoma multiforme (grade (IV) -Pilocytic astrocytoma (I) -Pleomorphic xanthoastrocytoma (II) -Anaplastic pleomorphic xanthoastrocytoma (III) n nOligodendrogliomas -Oligondendroglioma (II) -Anaplastic oligodendroglioma (III) n nMixed gliomas (provisional entities according WHO 2016) -Mixed oligoastrocytoma (II) -Anaplastic mixed oligoastrocytoma (III) n nEpendymal tumors -Ependymoma (II) -Anaplastic ependymoma (III) -Myxopapillary ependymoma (I) -Subependymoma (I) High grade (HG) astrocytomas (AC) nAnaplastic astrocytoma (III) -Increased cellularity -Increased degree of anaplasia, nuclear pleomorphism, increased proliferative aktivity - nGlioblastoma (IV) -Necrosis and pseudopalisading -Vascular endothelial proliferation -Primary (in older) and secondary (in younger with history of LG AC) -Very poor prognosis - - Glioblastoma 20 Glioblastoma_(1) 7-13l Necrosis and pseudopalisading Vascular endothelial proliferation WHO 2016: integrated diagnosis nHistopathological diagnosis/typing n nHistopathological grading/WHO grade n nMolecular information n n Oligodendroglioma Glioblastoma_(1) 7-13l Oligodendroglioma 24-1.jpg Astrocytic Oligodendrocytic Oligoastrocytic Glioneuronal Phenotype of gliomas Grading of gliomas Cellularity Cytonuclear atypia Mitoses Microvascular proliferates Necroses Genotype of gliomas Mutations IDH1, IDH2 Codeletion 1p/19q Mutation H3K27M Mutation ATRX Oligodendroglioma (II) nWhite matter of cerebral hemispheres (most frequently frontal lobes) nWell circumscribed, gelatinous, gray masses, with cysts, hemorrhage, calcification nSheets of regular cells, clear halo of cytoplasm nDelicate network of anastomosing capillaries nPerineuronal satellitosis nLOH for 1p and 9q/IDH mutated nBetter prognosis than AC n + anaplastic oligodendroglioma (III): hypercellularity, nuclear anaplasia, mitotic activity, necrosis Oligodendroglioma Oligodendroglioma nPilocytic astrocytoma (I) -Often cystic, also solid -Usually circumscribed, arising from optic nerve to conus medullaris -Bipolar cells („hair cells“) + Rosenthal fibers and eosinophilic granular bodies -Often biphasic (fibrillary areas + loose microcystic pattern) -Usually first two decades - nPleomorphic xantoastrocytoma (II); anaplastic (III) -Temporal lobe of children and young adults -Neoplastic occasionally bizarre astrocytes, also lipidized -Necrosis and mitotic activity indicate higher grade Pleomorphic xantoastrocytoma SampleQ14 nEpendymoma (II) -Next to ependyma-lined ventricular system, 4th ventricle -First 2 decades affected -Solid or papillary masses; complete extirpation due to localization impossible -Small „blue“ cells, granular chromatin, dense fibrillary background, perivascular pseudorosettes and rosettes - nAnaplastic ependymoma (III) n nSubependymoma (I) -benign, slowly growing, intraventricular - nMyxopapillary ependymoma (I) -Filum terminale of spinal cord Ependymoma 7-16b Neuronal and mixed (glio)neuronal tumors nGangliogliomas (I-II) n nDysembryoblastic neuroepithelial tumor (DNET) -In temporal lobe -Associated with epilepsy -Usually grade I; gangliogliomas may be gr. II/III - nDysplastic gangliocytoma of the cerebellum (I) n nCentral neurocytoma (II) -LG neuronal neoplasms -Within vetricular system n Spectrum of long-term epilepsy associated tumors nUsually low grade, well differentiated, with low proliferating activity and low malignant potential, superficially localized (cortical or subcortical; frontal and temporal localization), mixed neuronal-glial tumors, expression of stem cell marker CD34 n nMixed neuronal-glial tumors : -Ganglioglioma (GI, rare GII-GIII) -Dysembryoplastic neuroepithelial tumor (DNET, GI) nOthers: -Pilocytic astrocytoma (GI) -Diffuse astrocytoma (GII) -Oligodendroglioma (GII) -Pleomorphic xanthoastrocytoma (GII) -Subependymal giant cell astrocytoma (GI ; associated with tuberous sclerosis) -Angiocentric glioma (GI) n n Ganglioglioma - well differentiated, slowly growing neuroepithelial tumor - neoplastic ganglion cells + neoplastic glial cells - WHO GI; higher grades very rare; >70 % in temporal lobe 24-1.jpg DNET - WHO GI, benign, usually supratentorial glial-neuronal neoplasms - in children and young adults - cortical location - complex columnar and multinodular architecture, „specific glioneuronal elements“ (bundles of axons lined by oligodendroglia-like cells+floating neurons) - - 22-1.jpg 22-2.jpg DNET NeuN immunohistochemistry Calcification in DNET 17062-07-40x Obrázek1-1 Obrázek4 Nodular architecture 23-2.jpg Composite glioneuronal tumour: DNET and ganglioglioma component Hermanova_OBR3B Hermanova_OBR3A Ganglioglioma component DNET component Pilocytic astrocytoma - WHO GI, relatively circumscribed, slowly growing, often cystic - histologically biphasic pattern (compacted bipolar cells and loose-textured multipolar cells + Rosenthal fibers and eosinophilic granular bodies) 26-1.jpg 26-2.jpg Subependymal giant cell xanthoastrocytoma N312 400x N312 400x str Pleomorphic eosinophilic tumour cells Elongated tumour cells forming streams - WHO GI; tuberous sclerosis complex - benign, slowly growing, arising in the wall of the lateral ventricles, composed of the large ganglioid astrocytes Oligodendroglioma Oligodendroglioma SampleQ14 Pleomorphic xantoastrocytoma - WHO GII, a diffusely infiltrating - WD glioma - cerebral hemispheres - deletions 1p and 19q - WHO GII - superficial localisations in cerebral hemispheres + involvement of meninges - pleomorphic lipidized cells Medulloblastoma (gr. IV) n20 % of brain tumors in children nIn the midline of cerebellum; 4th ventricle, hydrocephalus nWell circumscribed, grey nhypercellular, „small blue cells“, neuroblastic rosettes (Homer Wright rosettes) nHigh proliferation, mitoses nExpression of neuronal markers (synaptophysin, NF; GFAP+ cells, vimentin) nDissemination through the CSF n4 histological subtypes; 4 molecular subtypes nPrognosis in untreated dismal; with total excision and irradiation: 5-year survival rate as high as 75 % n n Histological subtypes of medulloblastomas Integrated diagnosis of medulloblastomas: -histopathological diagnosis/typing -genetic profiling – 4 molecular subtypes - Medulloblastoma C:\Documents and Settings\jirka\Plocha\dejavu - mbl, paragangliom\MBL\Brož\BrožHE.jpg Other embryonal tumors/ WHO gr. IV n nAtypical teratoid/rhabdoid tumors n (posterior fossa, supratentorially; under 5, dismal prognosis) n nEmbryonal tumor with multilayered rosettes, C19MC altered n nMedulloepithelioma n nCNS neuroblastoma/ganglioneuroblastoma n nCNS embryonal tumor n n n Other tumors of CNS nPrimary CNS lymphomas (DLBCL) n nGerm cell tumors -Midline structures, pineal region, suprasellar region -Teratomas; germinomas (similar to seminomas),… n nPineal parenchymal tumors -Pinealoblastomas (high grade tumors) -Pineocytomas (well differentiated) -Gliomas in pineal region Tumors of the meninges nMeningioma (meningothelial) n n - nonmeningothelial nMeningeal hemangiopericytoma (so-called) nSolitary fibrous tumors Meningioma (gr. I-III) nUsually well defined rounded masses, adjacent to dura; encapsulated, extension into bone (reactive hyperostotic changes); less common „en plaque“ growth n nGrade I meningiomas: n- meningothelial -fibroblastic -transitional -psammomatous -microcystic, secretory, angiomatous,…. - nGrade II meningiomas: -atypical, clear cell, chordoid n nGrade III meningiomas: n- anaplastic (malignant), rhabdoid, papillary Meningioma 27 1 2 1 menigocytes 2 psamommata nCraniopharyngeoma: -Arise from squamous cell rests (derived from Rathke pouch) in sellar region -Benign (gr. I), partly cystic epithelial tumor n nHemangioblastoma: -Sporadic or ass. with VHL sy (in younger) -Cerebellum (medulla, spinal cord,…., supratentorial, retinal in VHL) -Well circumscribed, cystic, with mural nodule(s) -Capillary-size and larger thin-walled vessels with intervening neoplastic „stromal cells“ (large polygonal, vaculated, lipid-rich, PAS+) - - Familial tumor syndromes with involvement of tumor suppressor gene (AD) nCowden syndrome -PTEN mutation -Dysplastic gangliocytoma of the cerebellum n nLi Fraumeni syndrome -Inactivation of p53 -Medulloblastoma n nTurcot syndrome -Mutations in APC or mismatch repair gene -Medulloblastoma or glioblastoma n nGorlin syndrome -PTCH mutations, upregulation of SHH -medulloblastoma nNeurofibromatosis type I -AD; neurofibromas (plexiform and solitary)+gliomas of optic nerve+pigmented nodules of iris-cutaneous hyperpigmented macules (café au lait spots) -Malignant transformation of neurofibromas -NF1 gene (17q11.2); neurofibromin n nNeurofibromatosis type II -AD; 8th nerve schwannomas and multiple meningiomas + gliomas, ependymomas of spinal cord + non-neoplastic lesions of Schwann cells, meningeal cells, hamartia -NF2 gene (22q12); merlin n nTuberous sclerosis complex -AD; hamartomas and benign tumors of the brain and other tissues: cortical tubers (epileptogenic), subependymal nodules, subependymal giant cell astrocytomas,…, + renal angiomyolipomas, retinal glial hamartomas, pulmonary lympangioleiomyomatosis, cardiac rhabdomyoma + cysts – cutaneous lesions (angiofibromas, subungual fibromas, hypopigmented lesions) -tuberin or hamartin genes mutated n nVon Hippel Lindau Disease -AD; hemangioblastomas + cysts (pancreas, liver, kidney) + renal carcinomas, pheochromocytomas -tumor suppressor gene – pVHL – 3p25-p26 Peripheral nerve sheath tumors nSchwannoma -benign, from neural crest-derived Schwann cell, component of NF2 -well circumscribed, encapsulated, attached to nerve; 2 patterns: Antoni A and Antoni B -often vestibular branch of 8th nerve; sensory nerves preferentially involved (trigeminus, dorsal roots,..); extradurally – large nerve trunks - nMalignant peripheral nerve sheath tumor -highly malignant, medium and large nerves affected; in NF1 - nNeurofibroma: -Cutaneous: localized, in dermis or subcucateously -Plexiform: infiltrating lesion growing within and expanding a peripheral nerve; NF1; potential for malignant transofrmation; significant neurologic deficits n Schwannoma 3 3 Diseases of peripheral nerves nInflammatory neuropathies nInfectious polyneuropathies nHereditary neuropathies nAcquired metabolic and toxic neuropathies nTraumatic neuropathies n Inflammatory neuropathies nImmune mediated neuropathies: Guillain-Barré syndrome – GBS (acute inflammatory demyelinating polyradiculoneuropathy) -Weakness in distal limbs, ascending paralysis, hospital intensive care before recovering normal function (up to 20 % long term disability); in some patients followed by a subacute or chronic course -Inflammation and demyelination of spinal nerve roots and peripheral nerves (radiculoneuropathy) -Infections or prior vaccination ass. with GBS -T-cell mediated immune response Infectious polyneuropathies nLeprosy (Hansen disease) -Lepromatous leprosy: Mycobacterium leprae invading Schwann cells -Segmental demyelination, remyelination, loss of axons; endoneurial fibrosis and multilayered thickening of perineurial sheats -Symmetric polyneuropthy; pain fibers (loss of sensation) -Tuberculoid leprosy: cell-mediated immune response to M. leprae – granulomatous inflammation in dermis, cutaneous nerves affected n nDiphteria (diphteria exotoxin; selective demyelination of axons) n nVaricella zoster virus (varicella zoster virus; following chickenpox virus persists in neurons and sesory ganglia with potential ractivation) Hereditary neuropathies nHereditary motor and sensory neuropathies (HSMN I-III,….) nHereditary sensory and autonomic neuropathies (HSANs) nFamilial amyloid polyneuropathies nPeripheral neuropathy accompanying inherited metabolic disorders HSMN nHSMN - Charcot-Marie-Tooth (peripheral myelin protein 22, myelin, connexin,… -Demyelinating neuropathy; usually AD -Repetitive de- and remyelinations (onion bulbs – Schwann cell hyperplasia) -Slowly progressive, progressive muscular atrophy (legs) , uscle weakness, pes cavus n nHSMN II (kinesin family member KIF1B) -Axonal form – loss of myelinated axons n nHSMN III – Dejerine-Sottas neuropathy -AR, genetically heterogeneous (the same genes as in HSMN I) -Enlarged peripheral nerves, trunk and limb muscles affected Acquired metabolic and toxic neuropathies nPeripheral neuropathy in adult onset diabetes mellitus (polyol pathway and nonenzymatic glycation of proteins involved) -Distal symmetric sensory or sensorimotor neuropathy -Autonomic neuropathy -Focal or multifocal asymmetric neuropathy -Loss of small myelinated fibers, also unmyelinated fibers -Thickening of endoneurial arterioles nMetabolic and nutritional neuropathies -Uremic neuropathy -Chronic liver disease, respiratory insuf., thyroid dysfunction -Thiamine deficiency (neuropathic beriberi) -Avitaminosis B12, B6, and E nNeuropathies associated with malignancy -Brachial plexopathy (apex of a lung), obturator palsy (pelvic tumors), cranial verve palsies (intracranial tumors,….) -Paraneoplastic effect (small cell ca of lungs, plasmocytoma) nToxic neuropathies -Heavy metals, lead, arsenic Tumors of autonomic nervous system nExtraadrenal paragangliomas (carotid body paragangliomas, vagal and other paragangliomas) -non-chromaffin paragangliomas, usually related to parasympathetic nervous system -Alveolar pattern, cell nests; chief cells and sustentakular cells -Also malignant forms - nExtraadrenal paragangliomas of sympathoadreal neuroendocrine system (anywhere from the pelvic floor to the neck) n nPheochromocytomas (adrenal paraganglioma) (production of katecholamins, hypertension, usually benign) n nGangliocytic paraganglioma (benign, in duodenum) - n n - Tumors of autonomic nervous system nNeuroblastoma and ganglioneuroblastoma -In children under 4 ys (85 %) -In adrenal gland or intra-abdominal sympathetic chain (70 %) and in thorax (at least 20 %) -„Small blue cell“ tumor, bulky, multinodular, hemorrhages and necrosis often, calcification, also pseudocystic, lobular or nesting pattern, fibrillary material between cells (neuritic cell processes) – neurofibrillary matrix, rosettes, chromatin: „salt-and- pepper“ appearance -Ganglioneuroblastoma – some cytodifferentiation or maturation with recognizable ganglion cells - nGanglioneuroma -In posterior mediastinum or retroperitoneum; some arising in adrenal gland -Patient over 10 ys -Well, circumscribed, with no necrosis or hemorrhages, on cut surface whorled or trabecular pattern -Spindle cell matrix and mature ganglion cells n Pheochromocytoma feochromocytom 2 2 2 Neuroblastoma 1 1 Thank you for your attention …