Clinical Aspects of Brain Clinical Aspects of Brain TumoursTumours

Master of Science in Neurological SciencesDanny TM ChanNeurosurgeryOct 29 2012

Brain Tumors

• Classification– Histological / Pathological

– Clinical / Anatomical

Classification of Brain TumorsClassification of Brain Tumors

• Primary – Benign : Meningioma 20%– Malignant : Glioma 30%

• Secondary (30%)– Commonest tumors in the brain– Lung /Breast /Skin– Colorectal /Kidney /Prostate /Gonadal– Unknown Primary (15% of all brain 2’)

NeoplasticNeoplastic

• Primary– Glioma

– Meningioma

– Neuroma

– Others

• Secondary– Metastasis

NeoplasticNeoplastic

• Primary– Glioma

– Meningioma

– Neuroma

– Others

• Secondary– Metastasis

Primary Brain Tumors

• Neuroectodermal– Glial cells– Astrocytoma– Oligodendroglioma– Ependymoma– Medulloblastoma

• Mesenchymal– Meningioma– Haemangioblastoma– Sarcoma

• Lymphoid– Lymphoma

• Nerve Sheath– Acoustic neuroma– Trigeminal neuroma

• Germ Cell Tumor– Germinoma– NG‐GCT

Classification of Brain Tumors

• Supratentorial– Metastasis, glioma, meningioma

• Infratentorial– Metastasis, glioma(ependymoma, medulloblastoma), meningioma, haemangioblastoma

• Specific locations– Pituitary / Sellar– Pineal– Cerebellar‐pontine angle

Symptoms & SignsSymptoms & Signs

• Raised intracranial pressure (ICP)– Headache / Nausea / Vomiting– Papilloedema– Coma

• Local (focal) brain dysfunction– Compression – Hemiparesis/hemianopia– Infiltration– Seizure– CN palsy

Pressure Effects

Seizures

Focal Effects Acute

Events

Systemic / hormonal Effects

Elevated ICPElevated ICP

• Mass (SOL)

• Edema

• Hydrocephalus

ICP

Volume

Kelly Monro Doctrine

Brain tissue

CSF

Blood

Tumor

Pressure Effects

Seizures

Focal Effects Acute

Events

Systemic / hormonal Effects

Function of BrainFunction of Brain

Vision

Motor & Sensation

Memory & Emotion

Language

Distribution of Control in BrainDistribution of Control in Brain Left brain‐Right sideRight brain‐Left side

Kernohan’s sign

Ipsilateral limb

False localising sign

Contralaterallimb weakness

False localizing sign

Weakness Weakness

Right RightLeft Left

Right

Kernohan’snotch

Left

Pressure Effects

Seizures

Focal Effects Acute

Events

Systemic / hormonal Effects

SeizureSeizure

• Focal– Jacksonian

• Generalized

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Indications for operationIndications for operation• To confirm the diagnosis

• Evidence of significant mass effect

• Relief of hydrocephalus

• Cytoreduction

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Preoperative InvestigationsPreoperative Investigations• CT scan

• Magnetic Resonance Imaging (MRI) or angiography (MRA)

• Digital subtraction angiography (DSA)

• Work‐up for primary disease

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General PreGeneral Pre‐‐Op TreatmentOp Treatment

• Observation• Dexamethasone• Anticonvulsant• Osmotherapy if acute deterioration

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Urgency of treatmentUrgency of treatment

• Depends on the mass effect of the tumour• The rate of growth • Associated hydrocephalus• Preserving function e.g. vision

Malignant Malignant GliomaGlioma

Classification :Typing & GradingClassification :Typing & Grading

••WHO 1993 WHO 1993 •• KleihuesKleihues, Burger & , Burger & ScheithauerScheithauer

Grade I   Grade I   ‐‐ PilocyticPilocytic AstrocytomaAstrocytomaGrade II  Grade II  ‐‐ Low Grade Low Grade AstrocytomaAstrocytomaGrade III Grade III ‐‐ AnaplasticAnaplastic AstrocytomaAstrocytomaGrade IVGrade IV‐‐ GBM (GBM (GlioblastomaGlioblastoma Multiforme)Multiforme)

Prognosis & Median survivalPrognosis & Median survival

• Glioblastoma

• Anaplastic glioma

• Low grade glioma

• Pilocytic glioma

• 9 Months

• 2 Years

• Long

• Good

TreatmentTreatment

Surgery + RadiotherapySurgery + Radiotherapy+/+/‐‐ ChemotherapyChemotherapy

SurgerySurgery

• AIM :Maximal removal of tumor without production of new neurological deficit.

• Gross total• Subtotal (Debulking)• Biopsy : Open vs stereotactic

SurgerySurgery

• Histopathology• Immediate palliation• Oncological control (Cytoreduction)• Facilitate adjuvant therapies

SurgerySurgery

• Gross total resection

• Subtotal resection

Ammirati 1987

Median SurvivalMedian Survival• 90 weeks

• 43 weeks

SurgerySurgery

Benefit of radical surgery Benefit of radical surgery isis

Positive but modestPositive but modest

Minimal Invasive NeurosurgeryMinimal Invasive Neurosurgerywith Maximal Safetywith Maximal Safety

Awake CraniotomyAwake CraniotomyBrain MappingBrain Mapping

SubcorticalSubcortical

Cortical Cortical 

Glioma

Infiltrative

Eloquent area

Tumor at eloquent area

• Maximal surgical removal

• Minimal neurological deficit

Contra‐indications

• Existing irreversible deficit– Hemiparesis– Dysphasia

• Children– Cooperation– Immature brain

Awake Patients ‐ Preparation

• Patient briefing & training– Psychological anticipation– Pain threshold– Intra‐operative sequence of events

fMRIfMRI –– RightRight handhand fMRIfMRI –– SpeechSpeech‐‐ReadingReading

fMRIfMRI –– SpeechSpeech‐‐NamingNaming

Images courtesy of Johann Wolfgang Goethe University Hospital, Frankfurt, Germany

MR Spectroscopy

Choice of TE

Cho Map

Cr Map

NAA Map

Formation of Metabolic Maps

CSI ‐ Example of CSI maps 

Choline Map

NAA Map

Axial Survey

Normal Glioma

TE = 136 ms

TE = 272 ms

TE = 136 ms

(1) Image(1) Image‐‐NavigationNavigation

Motor mapping

• Usually no need for intra‐Op ECoG

• Localisation of central sulcus– Anatomy & Neuronavigation– Phase‐reversal SSEP

•Strip electrode

(2) (2) Phase Reversal SSEPPhase Reversal SSEP

11

22

33

44

(3) Direct Cortical Stimulation(3) Direct Cortical Stimulation Motor mappingMotor mapping

• Cortical stimulation– Ojemann Cortical Stimulator– Bipolar / biphasic stimulation– PW – 1ms– Frequency 60Hz– Current : 0.5mA to 15mA (Max. 20mA)– Stimulation probe parallel to gyrus– Stimulation of parafalcine cortex – Lower limb

Speech Mapping

• Intra-Op ECoG– GRASS EEG electrodes holder – “the Crown”– Maximal stimulation current– Seizure threshold – After-discharges (Ads)

• Counting• Naming

– Flash cards / Computer slides• Stimulation for 5 sec• Stimulations between every other sildes• Speech disturbance

– Speech arrest (Anomia)– Delay– Substitution with wrong name or mispronunciation

• Repeat for confirmation

這是

這是

這是

Intra‐Op Seizure

• Prevention– Adequate to high normal range of AED– Intra-Op ECoG for Ads

• Seizure abortion– Iced saline (4’C) applied to cortex– Methohexital– Midazolam

Video

Glioma SurgerySeeing the invisible

5‐ALA (5‐aminolevulinic acid)

• Elicits synthesis and accumulation of fluorescent porphyrins within malignant glioma tissue

• More complete resections of contrast‐enhancing tumour(OR 3.28 95% CI 1.99‐5.40, p<0.0001)

Walter Stummer et al. 2006

5-ALA

PpIX

Indication and contra‐I

Indication• Malignant glioma for gross / near‐gross total removal

• Expected minimum residual disease

Contra‐I• Porphyria/Pregnancy

• Debulking surgery• Pre‐existing fixed deficit

• Eloquent area (without mapping)

Usage

• 20mg/kg body weight• 3‐4 hours before surgery, orally• Active from 3rd ‐12th hr• Dark theatre : Ambient light : Neon tubes (red component)

• Photobleaching• Photosensitivity (24 hours)

Outcomes Assessment

• Primary outcomes– No. of patients without residual– 6‐month PFS

• Secondary outcomes– Post‐Op MRI residual volume– Overall survival– Neurological deficit– Toxic effects

Max. Rescetion vs Neurological deficit

• “It is the responsibility of the surgeon to decide how far he is prepared to remove fluorescing tissue”

• 5‐ALA fluorescence accumulation > contrast‐enhancement in MRI

Summary

5‐ALA is a surgical adjunct for maximum resection of malignant glioma.

However, it does not preserve function or avoid operative neurological deficit.

Instead it may increase the chance of neurological deficit in certain groups of patients without intra‐Op monitoring.

HK$2.5M

HK$25,000/1.5g HK~$561/g

Trained surgeon

Conclusion

• Maximal surgical removal of the maligantglioma provides modest benefit in survival and facilitates adjuvant therapies.

• Surgical risk should be balanced and neurological complications should be avoided as much as possible

• Awake craniotomy and cortical mapping is advised for tumor locating at or near eloquent cortex.

Intratumoral Chemotherapy

• Overcoming BBB• Increase local drug conc.• Minimizing systemic side effects• Sustain release drug for specific cell cycle phase

• Henry Brem 1995• Lancet• Prospective• Randomized• Placebo controlled• MS 31 vs 23 weeks

Local Chemotherapy ‐ Gliadel

• Biodegradable 1,3‐bis(2‐chloroethyl)‐1‐nitrosourea (BCNU) wafer

• Contains 3.85% BCNU to be release within 2‐3 weeks

• BCNU•Ability to cross blood‐brain barrier•Small fraction of dose at interested site with systemic 

toxicity • Prospective multi-centre, double-blinded, placebo-controlled trial

• Dec 1997 - June 1999

• n = 240

2‐3 years follow‐up

A “local” oncologist

Is it worth doing?

Brain Metastasis

BrainBrain

MetastasisMetastasis

Pathophysiology

• Destruction of BBB due to metastases result in tumour contrast enhancement and surrounding edema

EpidemiologyEpidemiology• Autopsy:  20‐40% of all cancer deaths have brain metastasis– Landis et al 1998: ~125,000  (American Cancer Society: 564,800 cancer deaths)

– More cancer in general in an aging populations

– Better imaging– Better control of primary disease

Primary TumourPrimary Tumour

• Relative multiplicity of brain metastasis varies with primary tumour

• Overall 30‐40% are solitary

19Breast13Melanoma4Renal1Unknown primary

25Others100Total

38Lung

% of brain metastasisPrimary tumour

Localization of metastatic Localization of metastatic tumorstumors

•Tumor emboli :80% in cerebrum, 15% in posterior fossa, 5% in brainstem•“Soil & seed”

SymptomsSymptoms

~ 40%Hemiparesis14%Cognitive impairment

12%Seizure7%Ataxia

16%Others~7%No symptom

40 - 50%Headache% of patientsSymptoms

•Up to two-third of all metastases are symptomatic at some time in life, due to raise ICP or neuronal damage•15% of cancer firstly presented with brain metastasis

Radiation Therapy Oncology Radiation Therapy Oncology Group (RTOG)Group (RTOG)

• 1200 patients from 1979‐1993 (WBI)–– Recursive Prognostic Analysis (RPA)Recursive Prognostic Analysis (RPA)

• a statistical methodology  which creates a regression tree according to prognostic significant

KPS <702.3 months3Not class 1 or 34.2 months2

KPS >= 70Controlled primary disease

Age < 65No systemic metastasis

7.1 months1

PatientsMedian SurvivalClass

Aggressive TreatmentsAggressive Treatments• Aggressive treatment with RS, MS, WBI

– Pollock BE J Neurooncol.2003– 52 patients from 1997‐2000

• Age: 58 y.o.;    KPS: 90;     Tumour no.: 3– Overall medium survival : 15.5 months– One year: 63% ;               Two years: 27%– Class 1 :  19 months   – Class 2 :  13 months    – Class 3 :  8 months

SuggestionAggressive treatments to class 1 and 2 patientswith controlled primary and limited no. of brain

metastasis

Aggressive TreatmentsAggressive Treatments• Surgical resection + WBI 

• Radiosurgery

• Until the 1990s, the role of surgical resection versus WBI for treatment of Single brain metastasis was an area of debate.

WBI or Surgery?WBI or Surgery?• Vecht CJ Ann Neurol 1993• Prospective randomized trial• 63 patients with single metastasis, stratified

9 months4 monthsFunctional independent survival

12 months7 monthsMedian survival

Surgery + WBI

WBI alone

Patient with progressive extracranial cancer carry poor survival (5 months) irrespective of treatment

Functional statusFunctional status improve rapid and longer than WBI

Surgery +/Surgery +/‐‐WBIWBI• Patchell RA (JAMA 1998)• Randomized trial:

– 95 patients post-op. :

– However, there’s no survival benefit

17/39 (44%)6/43 (14%)Death due to CNS cause17(37%)7(14%)other site21(46%)5 (10%)original site

32 (70%)9 (18%)Intracranial recurrence

Observe (46)WBI (49)

Stereotactic RadiosurgeryStereotactic Radiosurgery

Stereotactic RadiosurgeryStereotactic Radiosurgery

1. Stereotactic co‐ordinate system • Rigid head‐mounted frame• MRI / CT / DSA

2. Deliver single high dose radiation accurately focusing at the target• Rapid radiation dose fall off at boundary

Radiosurgery-Lethal hit vs Radiotherapy-Diff. repair

Stereotactic Radiosurgery – SRSStereotactic Radiotherapy – SRTConventional Radiotherapy

Types of RadiosurgeryTypes of Radiosurgery

• Gamma knife – Cobalt 60

• Linear Accelerator (LINAC) 

Current PracticeCurrent Practice• Treatment for resectable small (< 3cm) single brain 

metastasis is still under debate• Awaiting prospective randomized trial 

Risk of haemorrhage

Chemotherapy

Non-tolerateTolerate operationSystemic condition

AsymptomaticSymptomaticSymptomEloquentNon-eloquentLocation

<3cmLargeSize

RadiosurgerySurgery

Overall SurvivalOverall Survival

• Natural history:             1 month• With Steroid:                 2 months• WBI:                              3‐6 months• Surgery + WBI:             8‐12 months• Radiosurgery:      7‐12 months

Meningioma

• Commonest benign brain tumor• Arachnoid cap cell• Extra‐axial / shape margin / “dural tail”• Calcification / Hyperostosis• Locations

– Convexity / Parafalcine / Parasagittal– Olfactory groove / Sphenoidal ridge / Tentorial

Meningioma

Treatment for Meningioma

• Expectant policy

• Surgery

• Radiotherapy

Simpson Grade1. Total + Dura 9%2. Total + Coagulation 19%3. Total  29%4. Partial removal ~50%5. Biopsy >50%

Pituitary Tumor

• Anterior pituitary gland– TSH,ACTH,GH,FSH/LH,Prolactin

• Posterior pituitary gland– ADH, Oxytocin

Anatomy of pituitary gland

Optic chiasm

Carotid artery

CN

III

IV

V12

VI

Cavernous sinus

Sphenoid sinus

III ventricle

Anatomy of pituitary gland

Pituitary tumor

• Mass effect– Optic chiasm – Bitemporal hemianopsia– Third ventricle – hydrocephalus– Cranial nerves – III,IV,V,VI

• Hormonal disturbance– Functioning tumor– Non‐functioning tumor

Functioning tumor

• TSH• GH• ACTH• Prolactin• FSH/LH

• Hyperthyoridism• Acromegaly• Cushing disease• Galactorrhoea• rare

Acromegaly

DM / HT

Cardiomegaly

Carpal tunnel syndrome

Joints degeneration

Transphenoidal Surgery

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Transphenoidal approach for Pituitary tumour

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Acoustic Neuroma

• Benign tumour• arise from VIII nerve (Vestibular schwannoma)

• Difficult surgical assess

• Hearing loss

Acoustic Neuroma Acoustic Neuroma

• Hearing loss / Tinnitus / Dysequilibrium• Facial numbness / weakness• Abnormal corneal reflex / Nystagmus• Facial palsy (Rarely pre‐Op)

Treatment for Acoustic neuroma

• Expectant policy

• Radiation therapy

• Surgery

• Symptoms (Hearing)

• Size & Growth rate

• Patients

Neurofibromatosis type‐2 (NF2)

• Bilateral acoustic neuroma

• Chr. 22• Neurofibroma• Meningioma• Glioma• Schwannoma• Pheochromocytoma

The End