Cns tumors bikash

CENTRAL NERVOUS SYSTEM CENTRAL NERVOUS SYSTEM TUMORS IN CHILDRENTUMORS IN CHILDREN

CENTRAL NERVOUS SYSTEM CENTRAL NERVOUS SYSTEM TUMORS IN CHILDRENTUMORS IN CHILDREN

DR BIKASH RANJAN PRAHARAJ

Percentage Distribution of Childhood Cancers

INTRACRANIAL TUMORS (ICTS)

Primary or MetastaticOccur with equal frequency in adults, but in children primary tumors are far more common.Primary ICTs account for ~2% of cancers in adults 20% of all cancers in children.In children 70% of ICTs arise in Posterior fossa (infra-tentorial). asIn adults 70% of ICTs arise in Supra-tentorial.Cranial exposure to ionizing radiation is a risk factor.

Because of its location, a benign ICT may have fatal “malignant” effects.Malignant ICTs spread by: Direct infiltration of adjacent tissues May disseminate within the CNS via CSF.Gliomas account for 60% of primary ICTsMeningiomas for 20% & all others 20%.All CNS tumors behave as malignant clinically (Limited space)

Cytologic origin of CNS tumors

Neuro-ectodermalNeuro-ectodermal – most important are the – most important are the GliomasGliomas;;

MesenchymalMesenchymal – most frequent ones are the – most frequent ones are the MeningiomasMeningiomas;;

Ectopic tissuesEctopic tissues – from tissues „displaced” – from tissues „displaced” during embryogenesis: Ex., during embryogenesis: Ex., DermoidDermoid cyst; cyst;

Retained embryonal structuresRetained embryonal structures: various cysts – : various cysts – Paraphyseal cystParaphyseal cyst;;

MetastasesMetastases:: Lung, Breast, Melanoma, etc. in Lung, Breast, Melanoma, etc. in 50% of cases50% of cases

Neuro – ecto - dermal tumors

Glial cells:

astrocytes (A) - Astrocytoma

Oligodendroglial cells - Oligodendroglioma

Ependymal cells – Ependymoma

Neurons - Gangliocytoma

CLINICAL PRESENTATION

The unique features of CNS tumors – “ICP”

1. They grow in a unique environment: the intracranial space.2. The intracranial contents - incompressible Brain and blood contained within a rigid unyielding bony structure.3. Intracranial pathologies (tumors, abscess, hematoma, infarction, edema, etc.) eventually produce life threatening increase of the intracranial-pressure: ICP.

Increased Intracranial Pressure (ICP)

Headaches, progressively worsening

Vomiting (morning)

Irritability

Papilledema rare < 2 y/o - head can expand

“Double vision” with 6th nerve palsy

Head tilt

Bulging fontanelle (infant)

In a young child with ? brain tumor:In a young child with ? brain tumor:Measure head circumference and observe gaitMeasure head circumference and observe gait

Supratentorial Tumors

Signs depend on age and location:Younger child:

Developmental delay or loss of milestones

Older child: Deteriorating school performance Personality changes

Depending on location

Supratentorial tumours:

- Motor weakness

- Sensory changes

- Speech disorders

- Seizures

- Reflex abnormalities

- Hand preference

In midline/infratentorial tumours:- Classical triad of headache, nausea & vomiting

and Papilloedema- Blurred vision, nystagmus & diplopia- Disorder of equilibrium, gait & coordination.- Torticolis: in cerebellar tonsil herniation Diencephlic syndrome:- Failure to thrive- Emaciation & decreased appetite- Euphoric affect

Brain stem tumours:

- Gaze palsy

- Multiple cranial N palsies

- UMN deficits Optic N pathway tumours:

- Visual disturbances like decreased visual acuity, marcus gunn pupil, nystagmus & visual field defects

Suprasellar & 3rd Ventricle region tumours

Leads to neuroendocrine disturbances like DI Galactorrhoea Precocious puberty Delayed puberty Hypothyroidism

Perinaud syndrome: - Tumour of pineal region- C/F : paresis of upward gaze, pupillary dilation, reactive

to accommodation,not to light,eyelid retraction

Spinal cord tumours:

- long N tract motor &/or sensory deficits

- Bowel & bladder deficit

- Radicular or back pain

Seen in kids with increased cellularity

ASTROCYTOMASAccount for ~ 80% of primary ICTS in adults

MC in the cerebral hemispheres

MC Symptoms: headaches, seizures, focal neurologic deficits ( usually in the anterior or middle)

Low-grade Astrocytomas: Gross:

Poorly defined gray-white infiltrative tumors.

Histology: Hypercellularity; astrocytic nuclei of mild degree of atypia & astrocytic processes fibrillary background = fingers of

astrocytes

Low-grade Astrocytomas

Pilocytic Astrocytomas: MC in the cerebellum of children & young adults; and

less commonly in the optic nerve, hypothalamic region or cerebral hemispheres

Morphology:Cystic, with a tumor nodule in the wall of the cyst.Composed of bipolar astrocytes, with long hair-like processes, Rosenthal fibers & Micro-cysts+ calcification = good prognosis

Grow very slowly (some patients have survived for >40 yrs after incomplete resection) & have an Excellent prognosis

DD: not to confuse with low grade Fibrillary Astrocytoma

Rosenthal fibers

Gr. III. astrocytoma

Gr. IV. astro ~ = GBM

GBM: necrosis/pseudo-palisade

Pseudo pallisding central necrosis with perpendicular cells

Adverse prognostic factors in pt with high grade Astrocytoma

Older age Histologic f/o glioblastoma Poor karnofsky performance status Unresectable tumour Pt with unmethylated MGMT

Glioblastoma Cerebri

Highly infiltrating, non enhancing tumour involving more than 2 lobes

Histologically different from Glioblastoma but behave aggressively & has poor outcome

T/t: RT + Temozolamide

OLIGODENDROGLIOMA

Comprise ~ 5 -15% of GliomasArise in the cerebral white matter MC in the 4th & 5th decadesGross: Well circumscribed, gelatinous, gray masses, with foci

of hemorrhage & calcification.

Histology: Sheets of cells with rounded nuclei surrounded

by a halo of clear cytoplasm (fried egg appearance).

There is often a delicate network of capillaries & scattered foci of calcification (psammoma bodies)

Grows slowly, presents commonly with seizures, prognosis is better than Astrocytoma, average survival is 5-10 yrs (with modern therapeutic approaches)

Oligodendroglioma

EPENDYMOMA

Arise from the Ependymal lining of the ventricles or the central canal of the spinal cord Arise in the Fourth ventricle in children & young adults Spinal cord in the middle aged.Morphology: Highly cellular, tumor cells have regular nuclei May exhibit epithelial features with formation of

“rosettes” (Flexner Landsteiner) also perivascular pseudo-rosettes (homer Wright)

Most tumors are well differentiated

4th ventricle tumors: May cause hydrocephalus, usually can’t

be completely removed CSF dissemination may occur Average survival is ~ 4 yrs

Myxo-papillary Ependymomas

Arise in the filum terminale of the spinal cord Prognosis depends on completeness of surgical

excision

Ependymoma

““Rosettes” & perivascular Pseudo-rosettesRosettes” & perivascular Pseudo-rosettes

MEDULLOBLASTOMAS

Second MC ICT of childhood (after Astrocytomas).Occurs exclusively in the cerebellum.Derived from fetal external granular layer of cerebellum.Grows rapidly & occludes CSF flow hydrocephalus.

Seeds through CSF implants around the spinal cord & cauda equina (need irradiation of the whole Neuraxis).Histology: Extremely cellular, anaplastic, small round or

carrot-shaped cells with hyperchromatic nuclei, N/C, may form Homer-Wright pseudo-rosettes

Highly malignant, yet radiosensitive & 5-yr survival 75%.

Medulloblastoma

MedulloblastomaHomer-Wright pseudo-rosettesHomer-Wright pseudo-rosettes

carrot-shaped cellscarrot-shaped cells

MENINGIOMA

Usually Benign slow-growing tumors of adults, F/M 3:2Originate from meningothelial cells of the arachnoid.Usually solitary ( multiple meningiomas NF2 ) Morphology: Firm rounded masses, adherent to the dura and

compressing the underlying brain (no infiltration). Histologic variants include:

Syncytial, fibroblastic, transitional, Psammomatous & papillary ( propensity to recur).

Malignant Meningioma is very rare Infiltrates the underlying brain, shows

marked nuclear atypia, mitoses, & foci of necrosis.

Other rare sarcomas of meninges include: Hemangiopericytoma, malignant fibrous

histiocytoma & Fibrosarcoma.

Meningioma

MeningiomaSyncytialSyncytial PsammomatousPsammomatous Epithelial Membrane Antigen

NERVE SHEATH TUMORS1. Schwannomas:

Benign tumors of Schwann cells MC in the vestibular branch of the VIII CN at the cerebello-

pontine angle (acoustic neuroma) tinnitus & hearing loss Also involve branches of the trigeminal nerve & dorsal nerve

roots Tumors are encapsulated, attached to one side of the nerve;

axons do not pass through the tumor

Consist of Antoni -A areas of high cellularityAntoni -B myxoid areas

Schwannoma

Antoni – A hyprecellularAntoni – A hyprecellularAntoni –B Sparsely cellularAntoni –B Sparsely cellular

2. Neurofibromas: Benign tumors composed predominately of Schwann cells, but also

containing fibroblasts & perineural cells May involve single or multiple dorsal spinal nerve roots (multiple in

patients with von Ricklinghausen's disease – NF1) CN involvement is extremely rare May present as

Localized fusiform enlargement of a nerve or

Extensively infiltrate along the nerve “ropy enlargement” of the nerve & it’s branches (plexiform Neurofibroma) Plexiform neurofibromas are usually part of NF1, excision is

very difficult Histology:

Wavy spindle shaped cells, myxoid collagenous stroma with interspersed nerve fibers

„Acoustic Neurinoma” (Schwannoma)

METASTATIC ICTS

Very rare in children. Common Primaries: Broncho-genic small cell undifferentiated (oat cell) ca.,

Breast ca., Malignant melanoma, RCC. & Colon ca.Sites of metastases: Cerebral cortex 80%; Rest are in the cerebellum & brain stem.

50% are multiple; at the junction between the gray & white matter.

Vertebral column is a common site for metastases of Breast & Prostatic carcinomas Thoracic spine 60%, Cervical 20% & Lumbar 20%Treatment : Radiotherapy

CHOROID PLEXUS PAPILLOMA MC in children Arising from the lateral ventriclesIn adults they are found MC in the 4th ventricle Present with Hydrocephalus Due to either over-production of CSF or to

obstruction of the ventricular system.Consist of papillae with fibrovascular stalks covered with a cuboidal or columnar ciliated epithelium, recapitulating the structure of the normal choroid plexus.

COLLOID CYST OF THE THIRD VENTRICLEA non-neoplastic cystic lesionMorphology: Having a thin fibrous capsule, a lining of Cuboidal to

columnar epithelium & containing gelatinous Proteinaceous material.

Attached to the roof of the third ventricle at the foramina of Munroe & may cause sudden obstruction of the CSF flow acute non-communicating hydrocephalus brain herniation & deathSymptoms: headaches (often positional), “drop attacks”, incontinence Goblet cells are confirmatory

MISCELLANEOUS (MIDLINE) TUMORS

Pinealomas: True pineocytomas are extremely rare, may also have

pineoblastomas

Germinomas: MC in the pineal & suprasellar regions in adolescents &

young adults Closely resemble testicular Seminomas & ovarian

Dysgerminomas Other GCTs (Teratomas & Choriocarcinomas) also occur

Craniopharyngioma

Benign cystic tumors of children & adolescents

Develop in the suprasellar region Hypopituitarism

Originate from remnants of Rathke’s pouch & contain squamous & columnar epithelium

calcifications are common.

CNS LYMPHOMAPrimary CNS lymphomas

Account for ~1% of ICTs MC CNS neoplasm in AIDS & other

immunosuppressed patients often arise deep within the cerebral hemispheres & are commonly bilateral

Lymphoma cells exhibit an angiocentric distribution

Usually are B-cell lymphomas & many appear to be EBV-related.

PCNSL: Pathophysiology

Focal Lesion most common presentation: others include diffuse, uveal, leptomeningeal, and intramedullary.

Infiltrates normal brain diffusely.

Spreads along CSF pathways.

Rarely spreads outside the CNS.

Secondary CNS lymphomas

Lymphomas arising outside of the CNS rarely

involve the brain parenchyma

May involve the meninges, intradural spinal nerve

roots & epidural space

Leptomeningeal Carcinomatosis

Occurs in 5-8% of patients with solid tumors

Most common tumors to metastasize to the leptomeninges are small cell carcinoma (9-18%), and NHL (5-29%)

Other tumors include non-small cell lung, breast, melanoma, and G.U.

Leptomeningeal Carcinomatosis: Clinical Presentation

SYMPTOMS SIGNS

Headaches 33% Reflex assymetry(71%)

Lower Motor Weakness 38% Weakness 60%

Parasthesias 34%

Back/Neck Pain 26% Sensory Loss 27%

Radicular Pain 33% CN III Paresis 20%

Diplopia 20% CN VII Paresis 17%

Mental Status change 17%

Carcinomatous Meningitis

Diagnosis:

MRI

Cerebral Spinal Fluid

Rarely myelography

PHAKOMATOSES

Neurocutaneous syndromes ADHamartomas & Neoplasms

Esp. involving the nervous system & skin Mutations in tumor suppressor genes

1. Neurofibromatosis Type 1 (NF1): Neurofibromas, Neurofibro-sarcomas Optic nerve Gliomas Pigmented cutaneous macules (café au lait

spots) Pigmented nodules of iris (Lisch nodules)

2. Neurofibromatosis Type 2 (NF2): Bilateral Schwannomas of CN VIII Multiple meningiomas Spinal cord Ependymomas

3. Tuberous Sclerosis

Hamartomas (“tubers”) in the cerebral cortex, Sub-Ependymal hamartomas (“candle drippings”) & Sub-Ependymal giant cell Astrocytomas

Seizures & mental retardation

Extra CNS findings: Kidney (Angiomyolipoma), Heart

(Rhabdomyoma MCC in kids, adult = myxomas) , skin (Angiofibroma)

Tuberous Sclerosis

4. von Hippel-Lindau disease

Hemangioblastomas of the cerebellum, retina, brain stem & spinal cord

Cysts of liver, kidney & pancreas

incidence of RCC, may be bilateral

~ 10% of Hemangioblastomas polycythemia

Total surgical removal is curative

Von Hippel-Lindau disease

HemangioblastomasHemangioblastomas

DIAGNOSISDIAGNOSIS

Evaluation on emergency basis Complete history, physical examination &

neurologic assessment with neuroimaging For primary tumours: MRI with gadolinium

contrast is the gold standard. Low grade glioma: FLAIR MRI MRI better than CT: Tumor of suprasellar,

optic path, infratentorial & pituitary region

Specific investigations Neuroendocrine dysfunction evaluation : in tumor

of suprasellar,midline, pituitary & optic chiasmal region

Serum & CSF bHCG and AFP: germ cell T Lumbar Puncture:

- Indication: Medulloblastoma, ependymoma & germ cell tumours

- C/I : newly dx hydrocephalous sec. to CSF flow obstruction, tumour causing supratentorial midline shift & infratentorial tumours.

MANAGEMENTMANAGEMENT Multimodal i.e. surgery +/- chemoradiation Symptomatic & definitive Definitive:- depends on specific tumour

type

Symptomatic

Glucocoticoids: decrease perilesional edema & improve neurologic function

- DexamethasoneDexamethasone is the DOC bcoz of low mineralcorticoid activity

Seizure: anticonvulsants- leviteracetam, topiramate, lamotrigine, valproic acid &

Lacosamide- Phenytoin & carbamazepine should be avoided as

they may hamper the action of chemo bcoz they are enzyme inducers.

Venous thromboembolism:

- Ass. With 20-30 % patients with high grade glioma & brain metastasis

- Anticoagulants should be used prophylactically

Astrocytoma: Surgical Treatment

Accurate histological grade Palliation of mass effect

? Improved quality of life

Decreased dexamethasone requirement

? Impact on overall survival Retrospective studies say yes

No prospective, randomized trials

Advantages of Large Resection

Radiation Therapy & Chemotherapy

Chemotherapy following external beam radiation is advantageous in adults with anaplastic gliomas. Much less benefit is seen in patients with glioblastoma.

The few glioblastoma patients who benefit tend to be those that live the longest, suggesting that treatment preferentially benefits patients with favorable prognostic factors (i.e. young age, good P.S., minimal post-op, residual tumor).

Glioblastoma

Maximal surgical resection f/b

Partial field external beam radiotherapy with concomittant Temozolamide f/b

6-12 months of adjuvant Temozolamide In c/o recurrence: reoperation, BCNU/

bevacizumab

Temozolomide

Active metabolite of DTIC

Crosses the blood-brain barrier

Oral dosing: 200mg or 150mg/m2/x5d q4 weeks

Well tolerated: nausea/vomiting, myelosuppression

Idiosyncratic myelosuppression

Temozolomide

Indications: Relapsed Gr III anaplastic gliomas

Grade IV glioblastoma multiformae

Role in initial therapy uncertain: Probably equivalent to nitrosourea or PCV for high

grade gliomas Role as a radiosensitizer highly questionable(?) effective in oligodendroglioma.

Oligodendroglioma: Treatment

Complete surgical resection optimal Radiation therapy of questionable benefit Anaplastic oligodendrogliomas are chemosensitive tumors:Active regimens include: Single agent nitrosoureas PCV Temozolomide Other alkylating agentsChromosomal karyotypes may help predict therapeutic and clinical outcomes.

PCNSL: Treatment

For Diagnostic purposes only; extensive resection contraindicated.

Histologic diagnosis may be difficult from a stereotactic biopsy.

Surgery

PCNSL: Radiotherapy

Historically standard Tx

80% radiographic CR

14-18 month median survival

PCNSL: Treatment

Methotrexate (high-dose)Procarbazine, CCNU, VincristineBCNU

Ara-CCyclophosphamide, Adriamycin,Vincristine, Prednisone (“CHOP”). Decadron

••Multiple drugs shown to have anti-PCNSL activity

• PCNSL recurrent after radiation is often chemotherapy sensitive, although few (if any) are cured.

• Drugs should possess anti-lymphoma activity and have at least some ability to traverse a partially disrupted, if not intact BBB

Brain Metastases: Treatment

Solitary MetastasesGoals:

1. Palliate neurologic symptoms

2. Decrease future neurologic morbitiy

3. Prolong Survival

4. Potentially “cure” selected patients

Treatment:

1. Surgery if medically and anatomically indicated.

Brain Metastases: Treatment

Multiple MetastasesGoals:

1. Palliate neurological symptoms

2 Decrease future neurological morbidity

3. Prolong survival in selected patients

Treatment:

1. Whole brain XRT

2. Chemotherapy for chemosensitive tumors (i.e. breast cancer, small cell lung carcinoma)

Leptomeningeal Carcinomatosis

Goals of Treatment:

Destroy circulating and perineural

neoplastic cells to stabilize or improve

neurologic dysfunction.

Prolong survival in specific tumor types

(lymphoma, leukemia, breast carcinoma).

Leptomeningeal Carcinomatosis

Radiation

Involved field for acute cranial or spinal nerve involvement

No cranial-spinal

Chemotherapy

Intra-CSF: Intrventricular vs. Intrathecal (MTX, ara-C, Depocyte, Thiotepa) Ease of administration Patient Comfort Optimal CSF drug distribution

Systemic (?)

Treatment:

Spinal Cord Compression

DexamethasoneSurgical Decompression

LaminectomyAnterior resection

Radiotherapy treatment of choice.

Treatment:

Spinal Cord Compression

Indications for Surgical Interventions:Chance of restoring/preserving neurological function (anterior resection)*Initial presentation from an unknown neoplasm.Previously irradiated field. *Vertebral instability. *Progressive neuroloic deteriation during and following XRT. * Intractable pain despite adequate XRT, steroids, and analgesics.

* The decision to surgically intervene ultimately depends on an estimate of the morbidity of surgery versus the potential for significant quality survival.

Take home points

Brain tumors are second most common Brain tumour with best prognosis in

children is JPA & worst prognosis : Brain stem Gliomas

Over 70% of children diagnosed with

cancer can be cured of their disease. Management is through multimodal

approach

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