The Central The Central Nervous System: Nervous System:

TumorsTumorsThe peripheral The peripheral nervous systemnervous system

Markéta HermanováMarkéta Hermanová

Tumor of the CNSTumor of the CNS

GliomasGliomas Chorioid plexus tumors Chorioid plexus tumors (papillomas and (papillomas and

carcinomas)carcinomas) Neuronal and mixed neuronal tumorsNeuronal and mixed neuronal tumors Embryonal tumors (poorly differentiated)Embryonal tumors (poorly differentiated) Pineal tumorsPineal tumors Meningeal tumorsMeningeal tumors Other primary tumors of CNSOther primary tumors of CNS Secondary (metastatic tumors – Secondary (metastatic tumors – lung, lung,

breast,…)breast,…)

GliomasGliomas Astrocytomas (AC)Astrocytomas (AC)- Diffuse astrocytomas (grade II) – LG AC (static, with slow progression)Diffuse astrocytomas (grade II) – LG AC (static, with slow progression)Variants: fibrillary, protoplasmic, gemistocytic, mixedVariants: fibrillary, protoplasmic, gemistocytic, mixed- Anaplastic astrocytomas (III)Anaplastic astrocytomas (III)- Glioblastoma multiforme (grade (IV)Glioblastoma multiforme (grade (IV)- Pilocytic astrocytoma (I)Pilocytic astrocytoma (I)- Pleomorphic xanthoastrocytoma (II-III)Pleomorphic xanthoastrocytoma (II-III)

OligodendrogliomasOligodendrogliomas- Oligondendroglioma (II)Oligondendroglioma (II)- Anaplastic oligodendroglioma (III)Anaplastic oligodendroglioma (III)

Mixed gliomas Mixed gliomas - Mixed oligoastrocytoma (II) and other mixed gliomas Mixed oligoastrocytoma (II) and other mixed gliomas

Ependymal tumorsEpendymal tumors- Ependymoma (II)Ependymoma (II)- Anaplastic ependymoma (III)Anaplastic ependymoma (III)- Myxopapillary ependymoma (I)Myxopapillary ependymoma (I)- Subependymoma (I)Subependymoma (I)

High grade (HG) High grade (HG) astrocytomas (AC)astrocytomas (AC)

Anaplastic astrocytoma (III)Anaplastic astrocytoma (III)- Increased cellularityIncreased cellularity- Increased degree of anaplasia, nuclear pleomorphism, Increased degree of anaplasia, nuclear pleomorphism,

increased proliferative activityincreased proliferative activity

Glioblastoma multiforme (IV)Glioblastoma multiforme (IV)- Necrosis and pseudopalisadingNecrosis and pseudopalisading- Vascular endothelial proliferationVascular endothelial proliferation- Primary (in older) and secondary (in younger with Primary (in older) and secondary (in younger with

history of LG AC) history of LG AC) - Very poor prognosis Very poor prognosis

+ Gliomatosis cerebri (III-IV)+ Gliomatosis cerebri (III-IV) – multiple regions, in some – multiple regions, in some cases the entire brain infiltrated by neoplastic cases the entire brain infiltrated by neoplastic astrocytes astrocytes

Glioblastoma multiformeGlioblastoma multiforme

Pilocytic astrocytoma (I)Pilocytic astrocytoma (I)- Often cystic, also solidOften cystic, also solid- Usually circumscribed, arising from optic nerve to Usually circumscribed, arising from optic nerve to

conus medullaris conus medullaris - Bipolar cells („hair cells“) + Rosenthal fibers and Bipolar cells („hair cells“) + Rosenthal fibers and

eosinophilic granular bodieseosinophilic granular bodies- Often biphasic (fibrillary areas + loose microcystic Often biphasic (fibrillary areas + loose microcystic

pattern)pattern)- Usually first two decadesUsually first two decades Pleomorphic xantoastrocytoma (II-III)Pleomorphic xantoastrocytoma (II-III)- Temporal lobe of children and young adultsTemporal lobe of children and young adults- Neoplastic occasionally bizarre astrocytes, also Neoplastic occasionally bizarre astrocytes, also

lipidizedlipidized- Necrosis and mitotic activity indicate higher gradeNecrosis and mitotic activity indicate higher grade

Oligodendroglioma (II)Oligodendroglioma (II) White matter of cerebral hemispheres (most White matter of cerebral hemispheres (most

frequently frontal lobes)frequently frontal lobes) Well circumscribed, gelatinous, gray masses, Well circumscribed, gelatinous, gray masses,

with cysts, hemorrhage, calcificationwith cysts, hemorrhage, calcification Sheets of regular cells, clear halo of cytoplasmSheets of regular cells, clear halo of cytoplasm Delicate network of anastomosing capillariesDelicate network of anastomosing capillaries Perineuronal satellitosis Perineuronal satellitosis LOH for 1p and 9qLOH for 1p and 9q Better prognosis than ACBetter prognosis than AC

+ anaplastic oligodendroglioma (III): hypercellularity, nuclear anaplasia, mitotic activity, necrosis

OligodendrogliomaOligodendroglioma

Ependymoma (II)Ependymoma (II)- Next to ependyma-lined ventricular system, 4th Next to ependyma-lined ventricular system, 4th

ventricleventricle- First 2 decades affectedFirst 2 decades affected- Solid or papillary masses; complete extirpation due Solid or papillary masses; complete extirpation due

to localization impossible to localization impossible - Small „blue“ cells, granular chromatin, dense Small „blue“ cells, granular chromatin, dense

fibrillary background, perivascular pseudorosettes fibrillary background, perivascular pseudorosettes and rosettesand rosettes

Anaplastic ependymoma (III)Anaplastic ependymoma (III) Subependymoma (I)Subependymoma (I)- benign, slowly growing, intraventricularbenign, slowly growing, intraventricular Myxopapillary ependymoma (I)Myxopapillary ependymoma (I)- Filum terminale of spinal cordFilum terminale of spinal cord

EpendymomaEpendymoma

Neuronal and mixed Neuronal and mixed neuronal tumorsneuronal tumors

Gangliogliomas (I-II)Gangliogliomas (I-II)

Dysembryoblastic neuroepithelial tumor Dysembryoblastic neuroepithelial tumor (DNET)(DNET)

- In temporal lobeIn temporal lobe- Associated with epilepsyAssociated with epilepsy- Usually grade I; gangliogliomas may be gr. II/III Usually grade I; gangliogliomas may be gr. II/III

Dysplastic gangliocytoma of the Dysplastic gangliocytoma of the cerebellum (I)cerebellum (I)

Central neurocytoma (II)Central neurocytoma (II)- LG neuronal neoplasmsLG neuronal neoplasms- Within vetricular systemWithin vetricular system

GangliogliomaGanglioglioma

DNETDNET

Embryonal tumors/poorly Embryonal tumors/poorly differentiated neoplasms (gr. IV)differentiated neoplasms (gr. IV)

Medulloblastoma Medulloblastoma (in cerebellum)(in cerebellum)

Supratentorial primitive neuroectodermal Supratentorial primitive neuroectodermal tumor (PNET), tumor (PNET), (in hemispheres) (in hemispheres)

Ependymoblastoma Ependymoblastoma (supratentorial, related (supratentorial, related or not realted to ventricles)or not realted to ventricles)

Atypical teratoid/rhabdoid tumors Atypical teratoid/rhabdoid tumors (posterior fossa, supratentorially; under 5, (posterior fossa, supratentorially; under 5, dismal prognosis) dismal prognosis)

Central neuroblastomaCentral neuroblastoma

Medulloblastoma (gr. IV)Medulloblastoma (gr. IV) 20 % of brain tumors in children20 % of brain tumors in children In the midline of cerebellum; 4th ventricle, In the midline of cerebellum; 4th ventricle,

hydrocephalushydrocephalus Well circumscribed, grey Well circumscribed, grey hypercellular, „small blue cells“, neuroblastic hypercellular, „small blue cells“, neuroblastic

rosettes (Homer Wright rosettes)rosettes (Homer Wright rosettes) High proliferation, mitosesHigh proliferation, mitoses Expression of neuronal markers (synaptophysin, NF; Expression of neuronal markers (synaptophysin, NF;

GFAP+ cells, vimentin)GFAP+ cells, vimentin) Dissemination through the CSFDissemination through the CSF Loss 17p (p53), MYC amplification; alteration of Loss 17p (p53), MYC amplification; alteration of

Notch, Hedgehog, WNT signalling pathwaysNotch, Hedgehog, WNT signalling pathways Prognosis in untreated dismal; with total excision Prognosis in untreated dismal; with total excision

and irradiation: 5-year survival rate as high as 75 %and irradiation: 5-year survival rate as high as 75 %

MedulloblastomaMedulloblastoma

Other tumors of CNSOther tumors of CNS Primary CNS lymphomas (DLBCL)Primary CNS lymphomas (DLBCL)

Germ cell tumors Germ cell tumors - Midline structures, pineal region, suprasellar Midline structures, pineal region, suprasellar

regionregion- Teratomas; germinomas (similar to Teratomas; germinomas (similar to

seminomas),…seminomas),…

Pineal parenchymal tumorsPineal parenchymal tumors- Pinealoblastomas (high grade tumors)Pinealoblastomas (high grade tumors)- Pineocytomas (well differentiated)Pineocytomas (well differentiated)- Gliomas in pineal regionGliomas in pineal region

Tumors of the meningesTumors of the meninges

Meningioma Meningioma (meningothelial)(meningothelial)

- nonmeningothelial- nonmeningothelial Meningeal hemangiopericytoma Meningeal hemangiopericytoma

(so-called)(so-called) Solitary fibrous tumorsSolitary fibrous tumors

Meningioma (gr. I-Meningioma (gr. I-IIIIII)) Usually well defined rounded masses, adjacent to dura; Usually well defined rounded masses, adjacent to dura;

encapsulated, extension into bone (reactive hyperostotic encapsulated, extension into bone (reactive hyperostotic changes); less common „en plaque“ growth changes); less common „en plaque“ growth

Grade I meningiomas: Grade I meningiomas: - meningothelial - meningothelial - fibroblastic fibroblastic - transitionaltransitional- psammomatous psammomatous - microcystic, secretory, angiomatous,….microcystic, secretory, angiomatous,….

Grade II meningiomas:Grade II meningiomas:- atypical, clear cell, chordoidatypical, clear cell, chordoid

Grade III meningiomas:Grade III meningiomas:- anaplastic (malignant), rhabdoid, papillary - anaplastic (malignant), rhabdoid, papillary

MeningiomaMeningioma

Craniopharyngeoma:Craniopharyngeoma:- Arise from squamous cell rests (derived from Arise from squamous cell rests (derived from

Rathke pouch) in sellar regionRathke pouch) in sellar region- Benign (gr. I), partly cystic epithelial tumor Benign (gr. I), partly cystic epithelial tumor

Hemangioblastoma:Hemangioblastoma:- Sporadic or ass. with VHL sy (in younger)Sporadic or ass. with VHL sy (in younger)- Cerebellum (medulla, spinal cord,…., Cerebellum (medulla, spinal cord,….,

supratentorial, retinal in VHL)supratentorial, retinal in VHL)- Well circumscribed, cystic, with mural nodule(s)Well circumscribed, cystic, with mural nodule(s)- Capillary-size and larger thin-walled vessels with Capillary-size and larger thin-walled vessels with

intervening neoplastic „stromal cells“ (large intervening neoplastic „stromal cells“ (large polygonal, vaculated, lipid-rich, PAS+)polygonal, vaculated, lipid-rich, PAS+)

Familial tumor syndromes with Familial tumor syndromes with involvement of tumor suppressor involvement of tumor suppressor

gene (AD)gene (AD) Cowden syndrome Cowden syndrome - PTENPTEN mutation mutation- Dysplastic gangliocytoma of the cerebellumDysplastic gangliocytoma of the cerebellum

Li Fraumeni syndromeLi Fraumeni syndrome- Inactivation of p53Inactivation of p53- MedulloblastomaMedulloblastoma

Turcot syndromeTurcot syndrome- Mutations in Mutations in APCAPC or mismatch repair gene or mismatch repair gene- Medulloblastoma or glioblastomaMedulloblastoma or glioblastoma

Gorlin syndromeGorlin syndrome- PTCHPTCH mutations, upregulation of SHH mutations, upregulation of SHH- medulloblastomamedulloblastoma

Neurofibromatosis type INeurofibromatosis type I- AD; neurofibromas (plexiform and solitary)+gliomas of optic AD; neurofibromas (plexiform and solitary)+gliomas of optic

nerve+pigmented nodules of iris-cutaneous hyperpigmented nerve+pigmented nodules of iris-cutaneous hyperpigmented macules macules (café au lait spots)(café au lait spots)

- Malignant transformation of neurofibromasMalignant transformation of neurofibromas- NF1NF1 gene (17q11.2); neurofibromin gene (17q11.2); neurofibromin

Neurofibromatosis type IINeurofibromatosis type II- AD; 8th nerve schwannomas and multiple meningiomas + gliomas, AD; 8th nerve schwannomas and multiple meningiomas + gliomas,

ependymomas of spinal cord + non-neoplastic lesions of Schwann ependymomas of spinal cord + non-neoplastic lesions of Schwann cells, meningeal cells, hamartiacells, meningeal cells, hamartia

- NF2NF2 gene (22q12); merlin gene (22q12); merlin Tuberous sclerosis complexTuberous sclerosis complex- AD; hamartomas and benign tumors of the brain and other tissues: AD; hamartomas and benign tumors of the brain and other tissues:

cortical tubers (epileptogenic), subependymal nodules, cortical tubers (epileptogenic), subependymal nodules, subependymal giant cell astrocytomas,…, + renal subependymal giant cell astrocytomas,…, + renal angiomyolipomas, retinal glial hamartomas, pulmonary angiomyolipomas, retinal glial hamartomas, pulmonary lympangioleiomyomatosis, cardiac rhabdomyoma + cysts – lympangioleiomyomatosis, cardiac rhabdomyoma + cysts – cutaneous lesions (angiofibromas, subungual fibromas, cutaneous lesions (angiofibromas, subungual fibromas, hypopigmented lesions)hypopigmented lesions)

- tuberin or hamartin genes mutatedtuberin or hamartin genes mutated Von Hippel Lindau DiseaseVon Hippel Lindau Disease- AD; hemangioblastomas + cysts (pancreas, liver, kidney) + renal AD; hemangioblastomas + cysts (pancreas, liver, kidney) + renal

carcinomas, pheochromocytomascarcinomas, pheochromocytomas- tumor suppressor gene – pVHL – 3p25-p26 tumor suppressor gene – pVHL – 3p25-p26

Peripheral nerve sheath Peripheral nerve sheath tumorstumors

SchwannomaSchwannoma- benign, from neural crest-derived Schwann cell, benign, from neural crest-derived Schwann cell,

component of NF2component of NF2- well circumscribed, encapsulated, attached to nerve; 2 well circumscribed, encapsulated, attached to nerve; 2

patterns: Antoni A and Antoni Bpatterns: Antoni A and Antoni B- often vestibular branch of 8th nerve; sensory nerves often vestibular branch of 8th nerve; sensory nerves

preferentially involved (trigeminus, dorsal roots,..); preferentially involved (trigeminus, dorsal roots,..); extradurally – large nerve trunks extradurally – large nerve trunks

Malignant peripheral nerve sheath tumorMalignant peripheral nerve sheath tumor- Highly malignant, medium and large nerves affected; in Highly malignant, medium and large nerves affected; in

NF1NF1 Neurofibroma: Neurofibroma: - Cutaneous: Cutaneous: localized, in dermis or subcucateouslylocalized, in dermis or subcucateously- Plexiform: Plexiform: infiltrating lesion growing within and expanding infiltrating lesion growing within and expanding

a peripheral nerve; NF1; potential for malignant a peripheral nerve; NF1; potential for malignant transofrmation; significant neurologic deficitstransofrmation; significant neurologic deficits

SchwannomaSchwannoma

Diseases of peripheral Diseases of peripheral nervesnerves

Inflammatory neuropathiesInflammatory neuropathies Infectious polyneuropathiesInfectious polyneuropathies Hereditary neuropathiesHereditary neuropathies Acquired metabolic and toxic Acquired metabolic and toxic

neuropathiesneuropathies Traumatic neuropathiesTraumatic neuropathies

Inflammatory neuropathiesInflammatory neuropathies

Immune mediated neuropathies:Immune mediated neuropathies: Guillain-Guillain-Barré syndrome – GBS (acute inflammatory Barré syndrome – GBS (acute inflammatory demyelinating polyradiculoneuropathy)demyelinating polyradiculoneuropathy)

- Weakness in distal limbs, ascending Weakness in distal limbs, ascending paralysis, hospital intensive care before paralysis, hospital intensive care before recovering normal function (up to 20 % long recovering normal function (up to 20 % long term disability); in some patients followed by term disability); in some patients followed by a subacute or chronic coursea subacute or chronic course

- Inflammation and demyelination of spinal Inflammation and demyelination of spinal nerve roots and peripheral nerves nerve roots and peripheral nerves (radiculoneuropathy)(radiculoneuropathy)

- Infections or prior vaccination ass. with GBS Infections or prior vaccination ass. with GBS - T-cell mediated immune responseT-cell mediated immune response

Infectious Infectious polyneuropathiespolyneuropathies

Leprosy (Hansen disease)Leprosy (Hansen disease)- Lepromatous leprosy:Lepromatous leprosy: Mycobacterium leprae invading Mycobacterium leprae invading

Schwann cellsSchwann cells- Segmental demyelination, remyelination, loss of axons; Segmental demyelination, remyelination, loss of axons;

endoneurial fibrosis and multilayered thickening of endoneurial fibrosis and multilayered thickening of perineurial sheatsperineurial sheats

- Symmetric polyneuropthy; pain fibers (loss of sensation)Symmetric polyneuropthy; pain fibers (loss of sensation)- Tuberculoid leprosy: Tuberculoid leprosy: cell-mediated immune response to M. cell-mediated immune response to M.

leprae – granulomatous inflammation in dermis, cutaneous leprae – granulomatous inflammation in dermis, cutaneous nerves affected nerves affected

Diphteria Diphteria (diphteria exotoxin; selective demyelination of (diphteria exotoxin; selective demyelination of axons)axons)

Varicella zoster virus Varicella zoster virus (varicella zoster virus; following (varicella zoster virus; following chickenpox virus persists in neurons and sesory ganglia with chickenpox virus persists in neurons and sesory ganglia with potential ractivation) potential ractivation)

Hereditary neuropathiesHereditary neuropathies

Hereditary motor and sensory Hereditary motor and sensory neuropathies (HSMN I-III,….)neuropathies (HSMN I-III,….)

Hereditary sensory and autonomic Hereditary sensory and autonomic neuropathies (HSANs)neuropathies (HSANs)

Familial amyloid polyneuropathiesFamilial amyloid polyneuropathies Peripheral neuropathy Peripheral neuropathy

accompanying inherited metabolic accompanying inherited metabolic disordersdisorders

HSMNHSMN HSMN - Charcot-Marie-ToothHSMN - Charcot-Marie-Tooth (peripheral myelin (peripheral myelin

protein 22, myelin, connexin,…protein 22, myelin, connexin,…- Demyelinating neuropathy; usually ADDemyelinating neuropathy; usually AD- Repetitive de- and remyelinations (onion bulbs – Schwann Repetitive de- and remyelinations (onion bulbs – Schwann

cell hyperplasia)cell hyperplasia)- Slowly progressive, progressive muscular atrophy (legs) , Slowly progressive, progressive muscular atrophy (legs) ,

uscle weakness, pes cavususcle weakness, pes cavus

HSMN II HSMN II (kinesin family member KIF1B)(kinesin family member KIF1B)- Axonal form – loss of myelinated axonsAxonal form – loss of myelinated axons

HSMN III – Dejerine-Sottas neuropathyHSMN III – Dejerine-Sottas neuropathy- AR, genetically heterogeneous (the same genes as in AR, genetically heterogeneous (the same genes as in

HSMN I) HSMN I) - Enlarged peripheral nerves, trunk and limb muscles Enlarged peripheral nerves, trunk and limb muscles

affectedaffected

Acquired metabolic and Acquired metabolic and toxic neuropathiestoxic neuropathies

Peripheral neuropathy in adult onset diabetes mellitus Peripheral neuropathy in adult onset diabetes mellitus (polyol (polyol pathway and nonenzymatic glycation of proteins involved)pathway and nonenzymatic glycation of proteins involved)

- Distal symmetric sensory or sensorimotor neuropathyDistal symmetric sensory or sensorimotor neuropathy- Autonomic neuropathyAutonomic neuropathy- Focal or multifocal asymmetric neuropathyFocal or multifocal asymmetric neuropathy- Loss of small myelinated fibers, also unmyelinated fibers Loss of small myelinated fibers, also unmyelinated fibers - Thickening of endoneurial arteriolesThickening of endoneurial arterioles Metabolic and nutritional neuropathiesMetabolic and nutritional neuropathies- Uremic neuropathyUremic neuropathy- Chronic liver disease, respiratory insuf., thyroid dysfunctionChronic liver disease, respiratory insuf., thyroid dysfunction- Thiamine deficiency (neuropathic beriberi)Thiamine deficiency (neuropathic beriberi)- Avitaminosis BAvitaminosis B1212, B, B66, and E , and E Neuropathies associated with malignancyNeuropathies associated with malignancy- Brachial plexopathy (apex of a lung), obturator palsy (pelvic tumors), Brachial plexopathy (apex of a lung), obturator palsy (pelvic tumors),

cranial verve palsies (intracranial tumors,….)cranial verve palsies (intracranial tumors,….)- Paraneoplastic effect (small cell ca of lungs, plasmocytoma) Paraneoplastic effect (small cell ca of lungs, plasmocytoma) Toxic neuropathies Toxic neuropathies - Heavy metals, lead, arsenicHeavy metals, lead, arsenic

Tumors of autonomic Tumors of autonomic nervous systemnervous system

Extraadrenal paragangliomasExtraadrenal paragangliomas (carotid body paragangliomas, vagal and other (carotid body paragangliomas, vagal and other paragangliomas)paragangliomas)

- non-chromaffin paragangliomas, usually related to parasympathetic nervous systemnon-chromaffin paragangliomas, usually related to parasympathetic nervous system- Alveolar pattern, cell nests; chief cells and sustentakular cellsAlveolar pattern, cell nests; chief cells and sustentakular cells- Also malignant formsAlso malignant forms Extraadrenal paragangliomas of sympathoadreal neuroendocrine system Extraadrenal paragangliomas of sympathoadreal neuroendocrine system

(anywhere from the pelvic floor to the neck)(anywhere from the pelvic floor to the neck) Pheochromocytomas (adrenal paraganglioma) Pheochromocytomas (adrenal paraganglioma) (production of katecholamins, (production of katecholamins,

hypertension, usually benign)hypertension, usually benign) Gangliocytic paraganglioma Gangliocytic paraganglioma (benign, in duodenum)(benign, in duodenum) Neuroblastoma and ganglioneuroblastomaNeuroblastoma and ganglioneuroblastoma- In children under 4 ys (85 %)In children under 4 ys (85 %)- In adrenal gland or intra-abdominal sympathetic chain (70 %) and in thorax (at least In adrenal gland or intra-abdominal sympathetic chain (70 %) and in thorax (at least

20 %)20 %)- „„Small blue cell“ tumor, bulky, multinodular, hemorrhages and necrosis often, Small blue cell“ tumor, bulky, multinodular, hemorrhages and necrosis often,

calcification, also pseudocystic, lobular or nesting pattern, fibrillary material between calcification, also pseudocystic, lobular or nesting pattern, fibrillary material between cells (neuritic cell processes) – neurofibrillary matrix, rosettes, chromatin: „salt-and- cells (neuritic cell processes) – neurofibrillary matrix, rosettes, chromatin: „salt-and- pepper“ appearancepepper“ appearance

- Ganglioneuroblastoma – some cytodifferentiation or maturation with recognizable Ganglioneuroblastoma – some cytodifferentiation or maturation with recognizable ganglion cells ganglion cells

GanglioneuromaGanglioneuroma- In posterior mediastinum or retroperitoneum; some arising in adrenal glandIn posterior mediastinum or retroperitoneum; some arising in adrenal gland- Patient over 10 ysPatient over 10 ys- Well, circumscribed, with no necrosis or hemorrhages, on cut surface whorled or Well, circumscribed, with no necrosis or hemorrhages, on cut surface whorled or

trabecular patterntrabecular pattern- Spindle cell matrix and mature ganglion cellsSpindle cell matrix and mature ganglion cells

PheochromocytomaPheochromocytoma

NeuroblastomaNeuroblastoma

Thank you for your attention …Thank you for your attention …