Diagnosis, Treatment & Management of Medulloblastoma

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Dr Vandana, cranio spinal irradiation, radiotherapy, medulloblastoma, cancer, radiation, treatment, diagnosis, management, natural history of medulloblastoma, signs & symptoms of medulloblastoma, current approach, future advancements

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  • 1. Presented By: Dr. VandanaDeptt. of Radiotherapy CSMMU, Lucknow

2. Introduction

  • The origin of Medulloblastoma is frommedulla( Latin for marrow),blastos(Greek word for germ) andoma( Greek for tumor);
  • means tumor of primitive undeveloped cells located inside the cerebellum.
  • Most common malignant primary brain tumor of child age group.
  • First described byHarvey CushingandPercival Baileyin 1930.
  • Initially described as spongioblastoma cerebelli - a soft, suckable tumor usually arising in the vermis of cerebellum.
  • In 1925, changed name to medulloblastoma - from medulloblast - a hypothetical multipotent cell.

3. Origin

  • A highly malignant primary brain tumor that originates in the cerebellum vermis or posterior fossa.
  • Arise in cerebellum and projects into 4 thventricle.
  • Originate from embryonal cells k/a medulloblastof cerebellar stem cells. The exact cell of origin, or medulloblast has yet to be identified.
  • It is currently thought that it arises from Germinative neuroepithelial cells in the external granular layer of cerebellum.

4. Anatomy

  • Posterior fossa contains hindbrain which consists of cerebellum, pons and medulla.
  • The cavity of hindbrain is fourth ventricle. This is bounded in front by pons and medulla and behind by cerebellum.
  • Thevermisseparates two lateral lobes or cerebellar hemspheres.
  • Because of the location of the fourth ventricle, ventral to the cerebellum, mass lesions or swelling of the cerebellum can cause obstructive hydrocepahalus.

Relevant Neuroanatomy 5. CSF Pathways

  • CSF is producedby modified ependymal cells in choroid plexus
  • It circulates from lateral ventricles into the third ventricle through the foramen of munro.
  • It then passes into the fourth ventricle through the narrow cerebral aqueduct.
  • From the fourth ventricle, it passes slowly through median aperture (foramen of magendie) and lateralforamina (foramen of luschka) and enters the subarachnoid space over brain and spinal cord.
  • It is reabsorbed into venous sinus blood via arachnoid granulations.

Lateral Ventricle Foramen of Munro Third Ventricle Foramen of Luschka Foramen of Magendie Central canal of Spinal Cord Subarachnoid Space 6. Epidemiology

  • Overall account~ 7% all braintumors
  • 10-20% of brain tumors in pediatric agegroup
  • 0.4%1% of all adult centralnervous system tumors
  • 40% of tumors of the posteriorfossa
  • Peak incidence at the age of5 6yrs In children and25yrs in adults
  • Approximately 20% of Medulloblastoma present in infants younger than 2 years old; .
  • male : female (3:2)

Figure:Distribution of pediatric central nervous system (CNS) tumors by location in the CNS and by tumor type. 7. Adult vs. Paediatric Medulloblastoma Child Adult Usual age ~ 4 - 8 yrs Median age ~ 24 - 30 yrs Shorter clinical History (~ 3 months) Longer history ( ~ 5 months) Classical type predominates Desmoplastic type relatively commoner Median cerebellar syndrome predominates Lateral cerebellar syndrome seen Biologically more agressive Biologically less aggressive Poorer resectability - median location Greater resectability - lateral location Higher surgical morbidity and mortality Lower surgical morbidity and mortality - impact of location and age Poorer RT tolerance Better RT tolerance Poorer long term survival Better long term survival 8. Natural History Arising in the midline cerebellar vermis (roof of the 4 thventricle) Grows into the 4 thventricle Fills into the 4 thventricle Spread around the 4 thventricle Invasion of ventricular floor Invasion of brain stem Invasion of brachium pontis CSF Spread Extra neural spread :Y oung age, males and diffuse subarachnoid disease 9. Mode of Spread

  • Contagiously-
      • cerebellar peduncle
      • Floor of forth ventricle
      • Ant-brain stem
      • Inf cervical spine
      • Sup- above tentorium
  • CSF(30%)
      • Intracranially
      • Leptomeninges
      • Spinal cord
  • Extraneural (5%) Most common CNS tumor to spread
      • Hematogenous
      • MC sites are Long Bones and Ribs(10-15%)
      • LN(4-6%)

10. Pathological Features

  • Highly cellular tumor
  • High N:C ratio
  • Cells arranged in typical Homer -Wright rosettes
  • Multiple histological subtypes
  • Classic medulloblastomas- 70-80%
  • Desmoplastic/nodular- 7%
  • Medulloblastoma with extensive nodularity (MBEN) - 3%
  • Anaplastic
  • Large Cell

WHO classification-2007large cell / anaplastic (LCA) 10% to 22%. 11.

  • Classic Medulloblastoma:denselypacked cells, hyperchromatic nuclei
  • Medulloblastoma with extensive nodularity (MBEN):occurs in infants and is associated with a good prognosis.

classic medulloblastoma medulloblastoma with extensive nodularity 12.

  • Large cell medulloblastoma:Large nuclei, abundant cytoplasm.
  • These large cells tend to mix with cells with nuclear pleomorphism and k/a anaplastic cells.
  • Diffuse anaplasia is associated with poor prognosis.
  • Desmoplastic/nodular: nodular, reticulin-free zones or pale islands. Surrounded by densely packed mitotically active cells.

large cell medulloblastomaanaplastic medulloblastoma 13. Chang Surgical classification 1969T1 Tumour < 3 cm in diameter and limited to classic position in vermis, roof of fourth ventricle, or cerebellar hemisphere T2 Tumour > 3 cm in diameter and further invading one adjacent structure or partially filling the fourth ventricle T3a Tumour further invading two adjacent structures or completely filling the fourth ventricle, with extensions into aqueduct or foramina of Magendie or Luschka with marked internal hydrocephalusT3b Tumour arising from the floor of fourth ventricle or brain stemand filling the fourth ventricle T4 Tumour penetrates aqueduct to involve third ventricle or midbrain or extends to cervical cord No N StageM0 No metastases M1 Microscopic evidence of tumour cells in CSF. M2 Macroscopic metastases in cerebellar and/or cerebral subarachnoid space and/or supratentorial ventricular system M3 Macroscopic metastases to spinal subarachnoidal space M4 Metastases outside the central nervous system 14. Clinical Features

  • Raised ICT:Due to obstructive or non communicating hydrocephalus
  • Pressure Syndrome: Nocturnal or morning head-ache, nausea and vomiting and papilledema.
  • Symptoms usually precede presentation by no more than 2 months.
  • Presenting symptoms are related to the age of the patient.
    • infants with open cranial sutures, irritability, anorexia, failure to thrive, macrocephaly and setting sun sign.
    • The younger, nonverbal patient presents with behavioral changes, listlessness, irritability, vomiting, and decreased social interactions.
    • Older children and adults complain of headache, especially upon awakening in the morning.
  • Decerebrate rigidity, head tilt, stiff neck s/o herniation

15.

  • Cerebellar Signs:
  • In children, tumor involve cerebellar vermis causes gaitataxia.
  • In Adults, desmoplastic variant arises in cerebellar hemisphere causing ipsilateral dysmetria.
  • Worsening handwriting ,difficulty with hoping or running, slurring speech and hypotonia.
  • Neighbourhood syndrome :focal deficit due to pressure effect.
  • Brain stem :diplopia, 6th cranial nerve palsy, positional dizziness, nystagmus, tinnitus, hearing loss, facial sensory and motor loss .
  • Leptomeningeal dissemination:
  • Rarely the symptoms are present.
  • Patients can complain of radiculopathy
  • Bone mets-pain
  • Extra neural site - lymph node.

16. Diagnostic Work up

  • Detailed Clinical history:Morning headaches, nausea, vomitting, confusion,visual changes, unsteady walking.
  • Physical examination:Gait, signs of raised ICT, double vision, stiff neck
    • General examination
    • CNS examination
      • Higher mental exam
      • Cerebeller exam
      • Sensory exam
      • Motor exam
      • Cranial N. exam
    • Ophthalmoscopy examination for papilloedema

17. Confirmation of diagnosis

  • NeuroRadiological examination
  • Biopsy

Resection of tumor VP Shunting + Biopsy High dose steroids +Neuro radiological examination Patient stable Medulloblastoma Histopathological examination Patient extremely somnolent 18. Neuro Radiological examination CT finding

  • Hyperattenuated, well-defined vermian cerebellar mass
  • Surrounding vasogenic edema
  • Cyst formation
  • Evidence of hydrocephalus

Fig: A,Axial noncontrast CT image demonstrates a large lobulated hyperdense round tumor ( arrow ) with an internal hypodense cavity. An ill-defined faintly hypodense band surrounding the hyperdense mass represents white matter edema. 19. MRI features : MRI is the gold standard.

  • Iso- to- hypointense relative to adjacent cerebellar vermis (T1 images)
  • Iso intense to slightly Hyperintense on T2 weighted images
  • Homogeneous enhancement (but may be irregular and patchy) following contrast
  • MRI with contrast enhancementis very sensitive for detection of tumor spread, metastatic seeding in the cranial and spinal subarachnoid spaces.

20. Fig:( B, ) non-contrast axial T1-weighted(C,)T2-weighted MR images; the solid portion of the tumor appears mildly hypointense on T1-weighting and mildly hyperintense on T2-weighting ( arrow ). Following intravenous gadolinium, an axial T1-weighted image( D, ) demonstrates irregular patchy contrast enhancement of the solid areas of the tumor ( arrow ). 21. Adult Medulloblastoma

  • Poorly defined masses located in the cerebellar hemisphere.
  • Cyst like regions are more commonly seen

Fig:( A,)Axial T2-weighted MR image demonstrates a poorly circumscribed mass with a heterogeneous signal pattern in the anteroinferior portion of the right cerebellar hemisphere. ( B,)After intravenous administration of gadolinium, the tumor demonstrates homogeneous contrast enhancement with well-circumscribed margins ( arrow ). Punctate intratumoral hypointensities represent enlarged vascular channels and/or focal calcifications. 22. Spinal MRI

  • Fig:Sagittal and axial MRI, T1 weighted Gadolinium contrast enhancementMedulloblastoma with metastatic spread to themeninges within the posterior fossa and with a large intramedullary deposit .
  • Most sensitive for spinal cord mets
  • Frequency of spinal seeding at diagnosis is 30-35%.
  • M.C.seen in the lumbosacral and thoracic areas and are best seen onpost-contrast T1-weighted images.
  • MRI spine should be obtained whenever possible pre-operatively orelse at least 2-3 weeks post-operatively.

23. Advantage of MRI over CT

  • Highly sensitive
  • High resolution in diagnosing posterior fossa tumor because of high quality coronal images without artifacts, associated with beam hardening through bone in CT.
  • Sagittal images can be used in RT planning.
  • MRI better delineates tumor induced edema.

24.

  • CSF examination:Important for staging
    • Lumber puncture:most common method for obtaining CSF.
    • cant be obtained pre-operatively because of raised ICT. More commonly obtained at 3 weeks post operatively. To avoid risk of misinterpretation due to post operative changes.
  • Routine Investigations:Hemogram, KFT, LFT, Serum electrolyte, Chest X-ray, USG abdomen (Not mandatory)
  • Skeleton imaging :In case of Bone mets.

25. Risk Factor

  • At diagnosis, 2/3 rd of patients are standard risk and 1/3 are high risk.
  • Standard Risk:5yr. Survival is more than 80%
  • High Risk:5 yr survival is 30-60%
  • M stage is a crucial staging component.
  • Several studies had shown that the T stage of the Chang's system did not correlate with survival- so replaced by the definition of thepost operative residual tumor volume concept .

Risk Factor Standard RiskHigh Risk Age > 3 yrs. < 3 yrs Residual Tumor < 1.5 cm 2(Complete or near total resection) > 1.5 cm 2(subtotal or biopsy) Mets M 0M 1- M 4 26. Treatment

  • Medulloblastoma is well managed by multimodalapproach.

27. Surgery

  • Surgery is usually the first step and mainstay of treatment.
  • Objective:
  • Remove or Reduce as much of the tumor's bulk as possible.
  • Relieve ICT & local pressure effect ,i.e. Shunting.
  • Tissue Diagnosis and staging Biopsy.
  • Suboccipital Craniotomy
  • Surgery is classified as:
  • No evidence of residual tumor at surgery and negative postoperative imaging : Gross total resection
  • > 90%:Total or near total
  • 51 - 90% : Subtotal resection
  • 11 - 50% :Partial resection
  • < 10% :Biopsy

28.

  • Complication
    • Edema in the brain
    • Hematoma
    • Aseptic meningitis
    • Cervical instability
    • Posterior fossa syndrome/ cerebellar mutism syndrome:
      • 15% of children
      • Difficulty inswallowing, truncal ataxia, mutism, and, less often, respiratory failure
      • noted after a 12 to 24 hour
      • often improve dramatically, sometimes over many months after surgery.
  • Advantage:
    • Longer recurrence-free interval (Gross total resection).Exception is Brainstem involvement .
    • restores natural CSF pathways.

29. VentriculoperitonealShunt

  • VP shunting done for hydrocephalous reduction if repeated drainage fails to release symptoms.
  • Complication:
  • Blood clot or bleeding in the brain
  • Brain swelling
  • The shunt may stop working and fluid will begin to build up in the brain again.
  • The shunt may become infected.
  • Infection in the brain
  • Damage to brain tissue
  • Seizures
  • Through VP shunt, tumor can spread.

30. RADIOTHERAPY

  • Highly radio-sensitive.
  • RT plays a central role.
  • Objective:
  • To treat microscopic cancer cells / residual tumor with the goal of reducing its size or stopping its progression.
  • Prevent or treat spread through CSF. Covering the entire subarachnoid space is an essential component in the management of medulloblastoma. So We do Craniospinal irradiation ( CSI ).

31. Cont

  • CSI is a very complex technique
  • Goal is to achieve uniform dosage throughout the subarachnoid space, encompassing the entire intracranial vault and spinal canal.
  • Fundamental is
    • the use of opposed lateral fields including the cranium and upper cervical spinal canal,
    • matching a posterior spinal field including the full spinal subarachnoid space with cranial field
    • in larger children, the upper posterior spinal field matching with a separate lower posterior spinal field

32.

  • Target Volume:
    • Entire brain and its meningeal coverings with the CSF
    • Spinal cord and the leptomeninges with CSF
    • Posterior fossa boost
  • Energy
    • 4-6 MV linac or Co 60
  • Portals
    • Whole Brain: Two parallel opposed lateral field.
    • Spine: Direct Posterior field
  • Scheduling of radiotherapy:
    • Starting time : within 28 days following surgery
    • Duration of treatment : 45 to 47 days

33.

  • Dose
  • CSI (Phase I)
    • 30- 36 Gy in 18 - 21 # over 4 weeks to the cranium @ 1.5-1.8 Gy per #
    • 30-36 Gy in 18-21 # over 4 weeks to the spine @ 1.5-1.8 Gy per #
  • Posterior fossa boost (Phase II)
    • 18-20 Gy in 10-11# over 2 weeks to the posterior fossa

34. PLANNING STEPS

  • Positioning
  • Immobilization
  • Simulation
  • Field arrangement
  • Matching of CSI
  • Aligning of spinal field
  • Implementation of plan

35. Patient position

  • Prone (preferred):
  • Supine:
    • More patient comfort.
    • I n-anaesthetic patient
  • Head position
    • Slightly extended and the shoulders pulled down
    • to avoid beam divergence into the mandibule & dentition.

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