EMBRYONAL BRAIN TUMORS IN CHILDRENDr. Evith Pereira

Dr. Amruta Padhye Moderator – Dr. D.B.Borkar

• Cancer in childhood is rare with only 1:600 children developing malignancy by the age of 15 years.

• 20 -25% of childhood tumors are of CNS origin

• This equates to 2.4 cases / 100,000 children per year

• Medulloblastoma• Atypical Teratoid/ Rhabdoid Tumours• Embryonal Tumors with Multilayered Rosettes• Primitive Neuroectodermal Tumor• Pineoblastoma• Pituitary blastoma

MEDULLOBLASTOMA

Introduction

• The origin of Medulloblastoma is from medulla (Latin for marrow), blastos (Greek word for germ) and oma (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 by Harvey Cushing and Percival Bailey in 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.

Origin• A highly malignant primary brain tumor that originates in the

cerebellum vermis or posterior fossa.

• Arise in cerebellum and projects into 4th ventricle.

• Originate from embryonal cells k/a medulloblast of 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.

Epidemiology• Overall account ~ 7% all brain

tumors• 10-20% of brain tumors in pediatric

age group• 0.4%–1% of all adult central

nervous system tumors• 40% of tumors of the posterior

fossa• Peak incidence at the age of 5 –6

yrs In children and 25 yrs 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.

Adult vs. Paediatric MedulloblastomaChild 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 relativelycommoner

Median cerebellar syndromepredominates

Lateral cerebellar syndrome seen

Biologically more agressive Biologically less aggressivePoorer resectability - median location Greater resectability - lateral location

Higher surgical morbidity andmortality

Lower surgical morbidity and mortality - impact of location and age

Poorer RT tolerance Better RT tolerance

Poorer long term survival Better long term survival

Natural HistoryArising in the midline

cerebellar vermis (roof of the 4th ventricle)

Grows into the 4th ventricle

Fills into the 4th ventricle

Spread around the 4th ventricle

Invasion of ventricular floor

Invasion of brain stem

Invasion of brachium pontis

CSF Spread

Extra neural spread :Young age, males and diffuse subarachnoid disease

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%)

Pathological Features

Highly cellular tumorHigh N:C ratioCells arranged in typical

Homer - Wright rosettesMultiple histological subtypes

1. Classic medulloblastomas- 70-80%

2. Desmoplastic/nodular- 7%

3. Medulloblastoma with extensive nodularity (MBEN) - 3%

4. Anaplastic

5. Large Cell

WHO classification - 2007

large cell / anaplastic (LCA) 10% to 22%.

• Gross• Well circumscribed, gray-pink, soft/friable. • well-circumscribedsoft, fleshy tumor with areas of softening & necrosisin the center.

• Classical Medulloblastoma.• M/E-• Highly cellular • sheets of anaplastic cells with scanty cytoplasm,• hyperchromatic nuclei, that are often elongated & crescent shaped or angulated.• Mitoses- abundant• Occasional Homer-Wright rosettes and perivascular pseudorosettes

• Homer-Wright rosettes (groups of tumor cells arranged in a circle around a fibrillary center). Similar rosettes are seen in adrenal neuroblastoma.

• Positive stains• NSE, synaptophysin, Vimentin, Desmin, Nestin• Focal GFAP.• Molecular / cytogenetics description• Isochromosome (17q) or 17p-• 5-30% overexpress c-myc or N-myc;• C-myc overexpression is associated with poor prognosis 

• Differential diagnosis• Lymphoma: diffusely infiltrates CNS until it mixes with normal and reactive

fibrillar cells

• PNET• Ependymoma

Desmoplasmic/nodular medulloblastoma•  nodular b/c of its architecture • desmoplastic because it is permeated by (reticulin) fibers that give it a firm

consistency• M/E-

• Round pale nodules of tumor separated by zones of darker tumor cells.

•  Paler tumor nodules showing a population of uniform round to oval cells on a pale pink fibrillary background.

• The cells have a more mature neuronal appearance and are less active mitotically.

• The surrounding darker tumor cells are more primitive appearing with brisk mitotic activity.

• Desmoplastic medulloblastoma has a better prognosis than the classic form

Medulloblastoma with extensive nodularity • M/E-• Low power view numerous pale islands• The nodules are composed of a uniform population of tumor cells. The background

is reticulin-free & rich in neuropil-like tissue. Mitosis is not significantly increased. The cells often show streaming in parallel rows

• Special stain-• Reticulin-rich areas of high cellularity

• Anaplastic Medulloblastoma • M/E-• Highly anaplastic nuclei • with high rate of mitosis & apoptosis. • Primitive looking cellswith nuclear molding.• Some are composed of large cells with rounded vesicular nuclei (i.e. no nuclear molding). • Poor prognosis. 

Molecular Pathogenesis

Genetic predisposition (syndromes)

MOLECULAR SUBGROUPS

Genetic predisposition (syndromes)

Gorlin syndrome (3-5 % MB cases)TURCOT SYNDROME (<1 % MB cases)Li-fraumeni syndrome

GORLIN SYNDROME

The most common syndrome associated with MB (3-5 %).

Autosomal dominant → germline mutation in patched-1(PTCH-

1).

PTCH-1 → over activate SHH pathway.

characterized by nevoid basal cell carcinoma & skeletal

abnormalities.

TURCOT SYNDROME

Brain tumour (MB) & familial adenomatous polyposis (FAP).FAB caused by autosomal dominant→ inactivation adenomatous

polyposis coli (APC) gene on chromosome 5.

APC is part of protein complex in the WNT signaling

pathway→ control cell proliferation and differentiation.

LI-FRAUMENI SYNDROME

Mutations in TP53 (17p13). Worse outcome.

MOLECULAR SUBGROUPS

MB divided into 4 groups based on:DNA copy number, mRNA expression profiles and Somatic copy number aberrations.

1.SONIC HEDGEHOG (SHH) pathway2.WINGLESS (WNT) pathway3. TP 53 mutations4. MYC / MYCN amplification.

SONIC HEDEHOG (SHH) pathway

Abnormalities in SHH pathway are present

in 30% of MB cases.

MB pathology usually desmoplastic.SHH up-regulate MYCN gene.

Tp53 mutations are present in 10-20 % of

SHH tumours.

WINGLESS (WNT) pathway

WNT tumours are seen in children and adults. Rarely in infants.It associated with the most favourable

prognosis WNT protein binds to its receptor→

destabilizes APC protein.Loss chromosome 6.

TP 53 MUTATIONS are present in 10-20% of

WNT and SHH MB and very rarely in the other

subtypes.

MYC / MYCN - amplification of MYC group

genes is associated with a worse prognosis.

Symptoms & signs

MB patients present with symptoms and signs of:

1. Increased intra cranial tension.

2. Cerebellar dysfunction

Weeks→ few months

Evaluation

History

Morning headache

Nausea & vomiting

Visual changes

Confusion

Unsteady walking

A combination of surgery, radiotherapy and chemotherapy

Multi modal approach

Child AdultUsual age ~ 4 - 8 yrs Median age ~ 24 - 30 yrs

Shorter History (~ 3 months) Longer history ( ~ 5 months)Classical type predominates Desmoplastic type relatively

commonerMedian cerebellar syndrome

predominatesLateral cerebellar syndrome seen

Biologically more aggressive Biologically less aggressivePoorer resectability

(median location)Greater resectability

(lateral location)Higher surgical morbidity and

mortalityLower surgical morbidity and

mortality Poorer RT tolerance Better RT tolerance

Poorer long term survival Better long term survival

Difference in treatment between child & adult

Treatment at relapse

Relapse occurs in 20 - 30 % following initial treatment.

Site of relapse:

Local→ 1/3 cases

Disseminated (brain and spine)→ 1/3 cases

Both local and disseminated (brain and spine)→ 1/3

Time: within 3 years (children) but late relapse in

(adults).

Collin’s Law states : • The period of risk for recurrence of embryonal chilhood

neoplasms = age of patient at diagnosis + 9 months.

Atypical teratoid / rhabdoid tumor

• Comprise 1-2% of all CNS tumours in childhood.• M:F – 1.9:1• Biallelic mutations in the SMARCB1 gene(encodes for INI1)• Infants and young children (mean age 17 months) • Tumours of cerebellum or CP angle• Usually supratentorial (cerebral or suprasellar)• Poor prognosis- Metastatic d/s and young age• Very aggressive with mean survival 11 months post-surgery• Metastasizes throughout CSF.

•Large and pleomorphic rhabdoid cells with abundant eosinophilic cytoplasm, often filamentous cytoplasmic inclusions and vacuoles •Eccentric round nuclei and prominent nucleolus •May have mucinous background •May have epithelioid features with poorly formed glands or Flexner-Wintersteiner rosettes

CYTOLOGY DESCRIPTION•Cells are large, round and plasmacytoid or rhabdoid•Also small, round, primitive, neural type cells with high N/C ratio •Apoptotic bodies, mitotic figures, marked necrosis •Variable dystrophic calcification

GFAP

EMA VIMENTIN

POSITIVE STAINS

Vimentin, EMA, smooth muscle actin

Cytokeratin, neurofilament Focal GFAP, variable

synaptophysin and chromogranin

DIFFERENTIAL DIAGNOSIS

•Choroid plexus carcinoma

•Composite rhabdoid tumors (with other component, usually INI1+)

•Ependymoma

•Occasional germ cell tumors

•PNET/medulloblastoma

SUPRATENTORIAL PRIMITIVE NEUROECTODERMAL TUMOR

•Rare tumor, usually cerebral hemisphere •Medulloblastoma like histology•Disseminate along CSF pathway•Usually infants and children •Uniformly small and densely hyperchromatic cells of entirely undiff appearance disposed in patternless sheets •Desmoplastic mesenchymal components, high mitotic rates, necrosis and cystic change.

Small blue cell tumor with round, hyperchromatic cells, abundant mitotic figures and fibrosis

With abundant neuropil and true rosettes.

POSITIVE STAINSCD99 (strong membrane staining) Focal GFAP

DIFFERENTIAL DIAGNOSISAnaplastic glioma Atypical teratoid/rhabdoid tumorCentral PNET/medulloblastomaLymphomaMelanomaRhabdomyosarcoma Small cell meningioma

EMBRYONAL TUMOURS WITH MULTILAYERED ROSETTES

•Amplification of a miRNA on chromosome 9(C19MC) and over expression of the RNA binding protein LIN28a.

•“Embryonal tumours with abundant neurophil and true rosettes (ETANTR)”

•Ependymomatous rosettes- Multilayered cells surrounding a lumen, patches of dense cellularity and areas of more differentiated tumour with abundant neurophil.

•Poor prognosis with early progression of disease and death.

Ependymomatous rosettes- Multilayered cells surrounding a lumen, patches of dense cellularity and areas of more differentiated tumour with abundant neurophil

LIN28A immunohistochemistry of ETANTR

FISH analysis the C19MC 19q13.42 probe (green signals)

PINEOBLASTOMA

•High Grade IV of IV •Second most common pineal gland tumor after germ cell tumor •Germ line mutations in either RB gene or DICER1•Presents with signs related to location of the tumour in the upper midbrain, with Parinaud’s syndrome (failure of up-gaze, pupils that react poorly to light but respond to accomodation, nystagmus and lid retraction)

•Hydrocephalus- main presenting complaint

•Usually < 20 years

•Frequent CNS metastases or spinal seeding - main cause of death

•5 year survival approx. 58%

•Poor prognostic factors: 7+ mitotic figures/10 HPF Presence of necrosis No neurofilament staining

Dense small nuclei and scant cytoplasm Homer-Wright rosettes Sheets of cells with high grade (anaplastic / undifferentiated) features including high N/C ratio with minimal cytoplasm and large hyperchromatic nuclei •Necrosis, mitotic figures •Homer-Wright or Flexner-Wintersteiner rosettes

Small blue cell neuroepithelial malignant tumor

Positive stainsNSE, synaptophysin, retinal S-antigen

Differential diagnosisGlial neoplasms: GFAP+

Medulloblastoma

Pineocytoma: better differentiated cells with more cytoplasm, smaller cells, no/rare mitotic figures

PITUITARY BLASTOMA

•First 2 years of life with Cushing’s syndrome with ophthalmoplegia

•Histopathology- Combi. of epithelial structures, small embryonal cells and secretory cells.

•Express synaptophysin and chromogranin

•High frequency of germ line DICER1 mutations

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