MEDULLOBLASTOMA

Medulloblastoma is a small cell neuroectodermal tumor of cerebellum
Origin -These neoplasms are thought to arise from one of the following cells
- Proliferating precursor cells of the external granule cell layer that persists until the end of the first year of life.

- Another possible origin is from cal bindin positive cell line that supplies both the stellate and basket cells of the internal granular cells layer as well as the purkinje cells.
- Another source is minute dysplasia of the cerebellar vermis.
Clinical features–
- Age – Usually affects first two decades of life but can occur later in life also
- Site – In children- Vermian median site.
- Adults-often lateral (hemispheric)
- Symptoms – cerebellar dysfunction and increased intracranial pressure. Some cases may have craniospinal dissemination.
- Increased intracranial pressure symptoms
  - Headache
  - Frequent nausea upon waking
  - Bouts of vomiting
  - Cerebellar ataxia
  - Gait disturbances
Molecular genetics–
- Most of the cases sporadic.
- Rarely they occur inheritable diseases associated with syndromes like
  - Gorlins syndrome-Mutation in PTCH
  - Turcot syndrome-mutations in APC
  - Li- fraumeni syndrome-Mutations in P53
  - Coffin-Siris-Syndrome
  - Rubin-Stein-Taybi sundrome
- Most common cytogenetic findings are
  - loss of all or part of chromosome 17p often associated with duplication and translocation of chromosome 17q
- Other cytogenetic abnormalities are
  - gains on chromosomes 1q, 2p, 4p, 1 and 19
  - losses of chromosomes 10 and 11
- In anaplastic and large cell tumors –
  - high level gains of chromosomes 8q and 2p in the region of N-myc and c-myc
- In medulloblastoma associated with Gorlins syndrome – losses of heterozygosity was found for chromosome 9q22.3-q31
- Abnormalities identified in two major signaling pathways are
  - Sonic hedge hog (SHH) pathway
  - Wingless (WNT) pathway
Radiologic finding:
- Solid and contrast enhancing masses on MRI
- Well circumscribed lesion arising from its roof descending into the fourth ventricle
- Calcifications are absent
- In desmoplastic variant, bunch of grapes appearance
- Cystic changes are rare
Gross findings:
- Pinkish or grey masses
- Soft and friable with necrosis
- Rarely cyst formation is seen
- Desmoplastic variant in lateral cerebellar hemispheres are oftencircumscribed and well demarcated with firm consistency
- They can spread laterally within the sub arachanoid space, literally “ice” the pial surface
WHO classification of medulloblastoma
- Genetically defined – 5 subtypes
- Histologically defined – 5 subtypes
Molecular subtypes
- WNT activated
- SHH activated and TP53 wild type
- SHH activated and TP53 mutant
- Group 3 ( Non WNT/non SHH)
- Group 4 ( Non WNT/non SHH)
Histological subtypes
- Classical
- Desmoplastic/ Nodular
- Extensive nodularity
- Large cell/ Anaplastic
- Medulloblastoma NO

Microscopic findings:

Extension into subarachnoid space is common
Tumor re enters the brain along perivascular (Virchow- robin) spaces or by directly penetrating the parenchyma
Most of the tumor is solid and the periphery of high grade lesions may permeate brain parenchyma.
This infiltration results in a distinctive pattern of palisading within the molecular layer, similar to that seen when stacked Homer-Wright resette are cut along their long areas.
Extensive geographic necrosis may be present and rarely perinecrotic pseudopalisading.
Collagenous stroma is absent
Though the tumor is cellular there is considerable intertumoral and intratumoral variation in cytologic and histologic features.
Histologic, cytologic and ultrastructural subtypes: Though they are divided into nodular/desmoplastic and non nodular or classic types, the tumors are more heterogenous. The six descriptive categories overlap.
- Classic, i.e, light microscopically undifferentiated.
- With neuroblastic or neuroral differentiation.
- With glial and mixed or glioneuronal differentiation.
- Nodular/desmoplastic features.
- With extensive nodularity.
- With anaplastic and/or large cell features.

Rarely they differentiated into muscle and melanotic elements termed as medullomyoblastoma and melanotic medulloblastoma.

Classic or undifferentiated medulloblastoma:
- Major proportion of tumors in children are classic i.e; non-nodular/desmoplastic.
- The term refers to light microscopic appearance.
- They vary considerably in cytologic atypia and mitotic activity.
Medulloblastoma with neuronal/neuroblastic differentiation

- Neuronal or neuroblastic differentiation is expressed into form of Homer –wright rosettes
- Mature ganglion cells with or without accompanying ganglioid cells.
- Medium sized neoplastic cells with neuronal qualities
- Large finely fibrillar areas (nodules) of Synaptophysin positive neuropil.
- Homer wright rosettes have a central fibrillar zone composed of delicate cytoplasmic processes emanating from surrounding cells. These cells and cores are immunoreactive for Synaptophysin and Tubulin.
- Ganglion cells lie clustered in small patches of fibrillar neuropil.
- Ganglioid cells are immature cells having smaller somewhat vesicular nuclei, with less conspicuous nucleoli and no perceptible Nissle substance.
- In tumors with neuroblastic rosettes irregular fibrillar zones composed of tumor cell processes that are neoplastic counter part of normal gray matter or neuropil may be seen.
- Perivascular fibrillar zones are also common in lesions.
Medulloblastoma with glial differentiation or mixed differentiation:
- Glial differentiation is marked by immune histochemical finding than by routine H & E staining.
- Nodularity is considered as neuronal differentiation.
Nodular /Desmoplastic medulloblastoma:
- This type has distinctive lucent areas (pale islands) with abundant internodular reticulin and also with collagenous stroma with dissecting cords of tumor cells simulating cirrhous carcinoma
- Medulloblastoma in adults are mostly nodular/ desmoplastic than non nodular.
- Florid desmoplasia is usually noted in medulloblastoma invading leptomeninges.
- Pale islands are present in about 1/3^rd of cases and represent neuroblastic or neurocytic differentiation. In some malignant medulloblastoma only rudimentary nodules are present.
- Along with pale nodules, internodular regions show increased cellularity, cytologic atypia and mitotic activity. Thin rim of reticulin surrounds the nodules and also it surrounds the individual cells or cluster of cells in internodular region
Medulloblastoma with extensive nodularity.
- Described recently where tumor shows entirely nodules without any internodular desmoplastic stroma tissue.
- These rare lesion comprises less than 2% of all medulloblastoma and is seen in children below 2 years of age.
- Nodules may be large oval, circular or parabolic large areas of neuropil with scattered ganglion cells and foci of calcifications can be seen.
- Streaming of uniform neoplastic neurocytes in neuropil like background with in nodules is prominent.
- Cells are monotonous with round and bland nuclei showing oligodendroglial like perinuclear halos.
Large cell and anaplastic medulloblastoma:
- Approximately 20to 25% of the Medulloblastoma are of this type
- Cells shows nuclear angulation, increased mitotic activity, nuclear moulding and nuclear hyperchromasia.
- Nuclear size is 3 folds larger than classical medulloblastoma cells.
- Cells are concentrated into homogenous nodules or lobules with in tumor tissue.
- Apoptosis may be seen in single cell or confluent lakes is prominent feature of both large cell and anaplastic lesion. Apoptotic areas may be calcified.
- “Cannibalistic” cell wrapping where the wrapping of one neoplastic cell about another, the latter often apoptotic is characteristic features.

Immunohistochemistry:

Medulloblastoma are almost always Synaptophysin positive particularly fibrillar cores of Homer wright rosettes and perivascular pseudorosettes and pale islands.
Delicate fibrillar and neuropil like matrix are immunoreactive for microtubule associated protein and class-III beta tubulin.
Reticulin – rich intra nodular tissue of the nodular /desmoplastic variant is Neurotropin receptor p75NTR.
Medulloblastoma with glial differentiation shows GFAP positivity. As the medulloblastoma contains reactive astrocytes they can also give GFAP positivity but should be differentiated from tumor cell differentiation. Usually glial differentiation in tumor is focal and shows only circumferential perinuclear staining.
Occasional medulloblastoma cells are immunoreactive for retinal S-antigen, a marker of photoreceptor differentiation

Grading and prognosis:

Lesion with desmoplastic and extreme nodularity are large aggressive
Histologic grading is assigned by giving one point to each feature like
- Presence of necrosis
- Desmoplasia
- Cytoplasmic processes
- Mitosis

Total score of 2 points of less than prognosis.

Grading by the presence or absence of differentiation – GFAP staining was a negative prognostic factor
Prognostically significant molecular features divide medulloblastoma into 3 categories
- High Trkc, low C-myc
- High Trkc, high C-myc
- Low Trkc,High C-myc

Prognosis deteriorates as one progresses through these combinations.

Differential diagnosis:

Ependymoma– medulloblastoma usually are more uniformly hypercellular than ependymomas and lack their wide spread fibrillarity and perivascular pseudorosettes which are GFAP positive. In medulloblastoma perivascular pseudorosette are Synaptophysin positive.
High grade glioma can be differentiated by GFAP.
Atypical Teratoid /Rhabdoid tumor– Differentiated by complex immunophenotyping.

MEDULLOBLASTOMA

Medulloblastoma is a small cell neuroectodermal tumor of cerebellum

Origin -These neoplasms are thought to arise from one of the following cells

Proliferating precursor cells of the external granule cell layer that persists until the end of the first year of life.

Another possible origin is from cal bindin positive cell line that supplies both the stellate and basket cells of the internal granular cells layer as well as the purkinje cells.

Another source is minute dysplasia of the cerebellar vermis.

Clinical features–

Age – Usually affects first two decades of life but can occur later in life also

Site – In children- Vermian median site.

Adults-often lateral (hemispheric)

Symptoms – cerebellar dysfunction and increased intracranial pressure. Some cases may have craniospinal dissemination.

Increased intracranial pressure symptoms

Headache

Frequent nausea upon waking

Bouts of vomiting

Cerebellar ataxia

Gait disturbances

Molecular genetics–

Most of the cases sporadic.

Rarely they occur inheritable diseases associated with syndromes like

Gorlins syndrome-Mutation in PTCH

Turcot syndrome-mutations in APC

Li- fraumeni syndrome-Mutations in P53

Coffin-Siris-Syndrome

Rubin-Stein-Taybi sundrome

Most common cytogenetic findings are

loss of all or part of chromosome 17p often associated with duplication and translocation of chromosome 17q

Other cytogenetic abnormalities are

gains on chromosomes 1q, 2p, 4p, 1 and 19

losses of chromosomes 10 and 11

In anaplastic and large cell tumors –

high level gains of chromosomes 8q and 2p in the region of N-myc and c-myc

In medulloblastoma associated with Gorlins syndrome – losses of heterozygosity was found for chromosome 9q22.3-q31

Abnormalities identified in two major signaling pathways are

Sonic hedge hog (SHH) pathway

Wingless (WNT) pathway

Radiologic finding:

Solid and contrast enhancing masses on MRI

Well circumscribed lesion arising from its roof descending into the fourth ventricle

Calcifications are absent

In desmoplastic variant, bunch of grapes appearance

Cystic changes are rare

Gross findings:

Pinkish or grey masses

Soft and friable with necrosis

Rarely cyst formation is seen

Desmoplastic variant in lateral cerebellar hemispheres are oftencircumscribed and well demarcated with firm consistency

They can spread laterally within the sub arachanoid space, literally “ice” the pial surface

WHO classification of medulloblastoma

Genetically defined – 5 subtypes

Histologically defined – 5 subtypes

Molecular subtypes

WNT activated

SHH activated and TP53 wild type

SHH activated and TP53 mutant

Group 3 ( Non WNT/non SHH)

Group 4 ( Non WNT/non SHH)

Histological subtypes

Classical

Desmoplastic/ Nodular

Extensive nodularity

Large cell/ Anaplastic

Medulloblastoma NO

Microscopic findings:

Extension into subarachnoid space is common

Tumor re enters the brain along perivascular (Virchow- robin) spaces or by directly penetrating the parenchyma

Most of the tumor is solid and the periphery of high grade lesions may permeate brain parenchyma.

This infiltration results in a distinctive pattern of palisading within the molecular layer, similar to that seen when stacked Homer-Wright resette are cut along their long areas.

Extensive geographic necrosis may be present and rarely perinecrotic pseudopalisading.

Collagenous stroma is absent

Though the tumor is cellular there is considerable intertumoral and intratumoral variation in cytologic and histologic features.

Histologic, cytologic and ultrastructural subtypes: Though they are divided into nodular/desmoplastic and non nodular or classic types, the tumors are more heterogenous. The six descriptive categories overlap.

Classic, i.e, light microscopically undifferentiated.

With neuroblastic or neuroral differentiation.

With glial and mixed or glioneuronal differentiation.

Nodular/desmoplastic features.

With extensive nodularity.

With anaplastic and/or large cell features.

Rarely they differentiated into muscle and melanotic elements termed as medullomyoblastoma and melanotic medulloblastoma.

Classic or undifferentiated medulloblastoma:

Genetically defined – 5 subtypes

Classical

Pale islands are present in about 1/3^rd of cases and represent neuroblastic or neurocytic differentiation. In some malignant medulloblastoma only rudimentary nodules are present.