PEDIATRIC TUMORS OF CENTRAL NERVOUS SYSTEM

Under the age of two years –
- Choroid plexus papillomas
- Anaplastic astrocytoma
- Teratomas
First decade
- Medulloblastomas
- Astrocytoma
- Ependymoma
- Craniopharyngioma
- Glioma
Metastases is rare, when they occur at this age metastases of a neuroblastoma are most frequent
Astrocytomas occur at any age, but glioblastoma multiforme is mostly seen in older people.

CHOROID PLEXUS PAPILLOMA:
- The choroid plexus are a secretory organ responsible for the production of CSF, consists of richly vascularized fibrous stroma lined by an epithelium derived from neuroectodermal cells
- Age : Most of these tumors appear in childhood
- Site : They can occur in any portion of choroid plexus, but are more common in the lateral ventricles of children and fourth ventricle of adults
- Tumors derived from the choroid plexus epithelium show considerable morphologic and biologic diversity
- Majority of them are benign neoplasms that replicate the villous architecture of the parent organ and are termed Choroid plexus papillomas (WHO grade I).
- Clinical and radiographic features include hydrocephalus
- The tumor must be larger than normal choroid plexus to diagnose choroid plexus papilloma because its microscopic features are very similar to normal choroid plexus
- Gross: Choroid plexus papilloma is a friable mass having villiform or bosselated surface, cystic lesions are exceptional.
- Calcifications are common.
- Microscopy: Complex array of branching fibrovascular fronds covered by a monolayer of uniform cuboidal/columnar epithelial cells with minimal nuclear atypia and little mitotic activity.
- In contrast to the “cobblestone” pattern of normal choroid plexus, papillomas typically display taller epithelial cells which lack apical intercellular separations. These cells rests on basement membrane, apices are joined by functional complexes and crowned by microvilli, may be ciliated.
- The stroma is infiltrated by foamy macrophages.
- Few foci show metaplastic bone or cartilage formation.
- The peculiar features is papilloma exhibiting overt neuronal differentiation signaled by micronodular collections of syn-rich matrix (choroid plexus papilloma with neuropil like islands).

- Immunohistochemistry: Cytokeratin, transthyretine positive for choroid plexus epithelial cells. Some express GFAP and some express synaptophysin.

- Differential diagnosis:

1. 1. Papillary variant of ependymoma:
    - Papillary ependymoma occurs in different location than choroid plexus papilloma
  2. Metastatic tumors including papillary variant of thyroid, breast, renal and ovarian carcinomas.
  3. Papillary meningioma.

- - - Mucin production, lack of whorls, lack of solid syncitial foci distinguish from papillary meningioma.

Atypical choroid plexus papilloma Grade-II:
- It is an interface between papilloma and carcinoma.
- Criteria is two or more mitotes/10 random HPF.

Choroid plexus carcinoma Grade-II:
- Very rare neoplasm.
- Consists of sheets of anaplastic cells with necrosis invasion, high proliferative activity.
- Papillary features may be difficult to distinguish.
- Primary carcinoma of choroid plexus closely resembles metastatic carcinoma so diagnosis should be made carefully.
- Papillary structure breaks down and replaced by nests and Pattern less sheets of anaplastic cells with pleomorphism and mitotic activity.

TERATOMA:
- CNS germ cell tumors arise from primordial germ cells that migrate to developing central neuraxis or as form native stem cell elements remains a speculative matter.
- Age: They occur in first two decades of life.
- Sex: Males are affected twice as frequently as females.
- CNS germ cell tumors generally are sporadic but are recognized to complicate Kleinfelter syndrome and their incidence may be increased in setting of Down’s.
- Suprasellar tumors produce visual field defects, Diabetes insipidus, and hypothalamopituitary failure. pineal region tumors produce obstructive hydrocephalus.
- Teratomas contribute the majority of congenital CNS germ cell tumors.
- This tumor group includes
  - mature teratoma
  - immature teratoma
  - Teratoma with malignant transformation.
- Sarcomas of undifferentiated or rhabdomyosarcomatous aspect, leiomyosarcoma, adenocarcinoma of enteric type, squamous carcinoma and erythroleukemia have been reported to arise from intracranial teratoma containing germ cell tumors.
- The spontaneous maturation of teratomas has been recorded.
- The progressive, paradoxial enlargement of these mature neoplasm has been referred to as “The growing teratoma syndrome”.
- Ki67/MIB-I assessment can demonstrate the levels of proliferative activity within the fully differentiated tissues of such recurrent lesions.

MEDULLOBLASTOMA (GRADE-IV):
- The medulloblastoma is a common primitive neuroectodermal tumor that arises in the cerebellum or in the roof of fourth ventricle.
- Age: It is most common in children but also in young adults rare in patients over 35 years.
- It is often associated with ischromosome 17q.
- Because it spreads along CSF, treatment should be directed at entire neuraxis.
- About 5% medulloblastomas metastalize to systemic location particularly to bone.
- Medulloblastoma is a small, round, blue cell tumor with marked hypercellularity, anaplastic nuclei and a high nuclear cytoplasmic ratio.
- Its neuronal phenotype is demonstrated by positivity of neoplastic cells for synaptophysin.
- Regardless of its other lines of differentiation, neuronal differentiation is a defining characteristic of medulloblastoma.
- Regions of glial differentiation can be noted histologically and confirmed by GFAP.
- Fibrillarity is extremely important to the diagnosis of medulloblastoma.
- The fibrillar cellular processes arise directly from neoplastic cells in medulloblastoma.
- Rosettes with cores filled with fibrils, Homer Wright rosettes in CNS are characteristic.

Differential diagnosis:
- Small cell carcinoma and lymphoma – Lack fibrillarity.
- Primary CNS lymphoma – Reactive fibrillar cells are seen, neoplastic cells do not have fibrillary process.

Variants:
- Desmoplastic medulloblastoma (Grade IV):
  - They have both abundant reticulin and crowded proliferating cells and pale islands of tissue that lack reticulin and are less crowded with cells.
  - These islands show neuronal markers like synaptophysin and low proliferation.
  - These islands are called reticulin free zones and give nodular appearance.
  - Non nodular desmoplastic medulloblastomas are also noted.
  - The nodularity is associated with better prognosis.

- Anaplastic and large cell medulloblastomas:
  - The medulloblastoma tumor showing large cells, nuclei and nucleoli have poor prognosis compared to other types of medulloblastoma.
  - These prognostic features are seen in large cell medulloblastoma (LCM).
  - They show many mitoses and apoptotic nuclei cells wrap around each other have ground or vesicular nucleus and conspicuous cytoplasm.
  - C-Myc distinguish LCM from other medulloblastomas.
  - Anaplastic medulloblastoma have same features of LCM.

- Medullomyoblastoma Grade IV:
  - Rare neoplasm, occurs in the midline posterior fossa of children.
  - These care mixture of stainable muscle cells and small neuroectodermal cells resembling medulloblastoma.
  - They contain smooth or straited muscle fibres.

Differential diagnosis:
- Primary intracranial rhabdomyosarcoma, which do not have neuroectodermal cells.
- Synaptophysin helps in detection of these neuroectodermal cells.

ASTROCYTOMA:
- Astrocytomas are a heterogenous group of neoplasms with numerous subtypes.
- The WHO classification of astrocytic tumors defines to principal tumor types that are usually grouped into two broad categories

- Category I has more malignant progression while category II tumor shave less capacity for malignant progression and do not show aggressive growth with diffuse invasion.

Pilocytic astrocytoma WHO grade I:
- They are most abundant in the posterior fossa, where they represent the majority of childhood astrocytomas
- They are also found around 3^rd ventricle, thalamus hypothalamus and neurohypophysis
- It has benign in nature
- Low grade tumor manifests both bipolar neoplastic cells with elongated hair like processes projecting from either end and other neoplastic cells with multiple processes.
- Pilocytic astrocytomas are often microcystic and may be macrocystic, in the cerebellum, the cysts can be quite large forming a mural nodule.
- This mural nodule and its solid counterpart are often very vascular resembling a hemangioblastoma.

- Immunohistochemistry: GFAP positive neoplastic astrocytes.
Pilomyxoid astrocytoma (PMA):
- Typically found in very young children.
- It has bipolar cells that cluster around vessels, but its parenchyma is more pilocytic than ependymomatous.
- Angiocentricity and its mucinous matrix characterize the PMA.

Diffuse astrocytoma:
- The term diffuse appropriately describes these neoplasms because their margin gradually diminishes in cellularity.
- Within the extensive margin, neoplastic cells intermingle with CNS parenchyma.
- These astrocytomas can be particularly difficult to distinguish from gliosis.
- Astrocytes are hyperchromatic and pleomorphic nuclei.
- They have diffuse growth and infiltration but seldom cured.
- Portoplasmic, fibrillary and gemistocytic astrocytomas all diffuse astrocytomas.

Protoplasmic astrocytoma:
- The diagnosis of protoplasmic astrocytoma is rare.
- They have small cell bodies, round to oval nuclei, few cellular processes and numerous microcytsts filled with faintly purple mucoid material.

Fibrillary astrocytoma:
- They are common.
- They are a mixture of cellular processes and nuclei of greater angularity and density than CNS parenchyma.
- They contain more cytoplasm and their cellular processes are longer with more glial fibrillary acid protein than protoplasmic astrocytoma.
Gemistocytic astrocytoma:
- Gemistocytes are astrocytes with a distended, hyaline, pink cytoplasm packed with GFAP fibrils, their nuclei are pleomorphic and often at rim of the cell.
- These neoplastic gemistocytes are distinguished from reactive gemistocytes by their nuclear hyperchromasia and elongation known as boomerang nuclei.
- These are clinically aggressive, can progress quickly to anaplastic astrocytoma and have poor prognosis.

- Differential diagnosis: Oligodendroglioma
Anaplastic astrocytoma Grade III:
- The anaplastic astrocytoma, IDH mutant WHO grade III often evolves from a well differentiated precursor lesion showing CDKN2A/B genes deletion that encode P^16,P¹⁵, and P¹⁴.
- The designation anaplastic emphasizes the grade of malignancy.
- Mitoses are considered a feature of anaplastic astrocytoma.
- The criteria established by WHO classification for anaplastic astrocyotma include focally or diffusely increased cellularity, nuclear atypia and mitotic activity.
- Endothelial proliferation and necrosis should not be present.
- In general anaplastic tumors have less dense fibrillary matrix than well differentiated astrocytomas.
- Approximately 40 % of glioblastomas and 10-20% of anaplastic astrocytomas have EGFR amplification, which never present in diffuse astrocytomas.
- The lack of foci of coagulation necrosis and lack of microvascular proliferation in an astrocytic glioma distinguishes anaplastic astrocytomas from glioblastoma but individual cells with pyknotic nuclei may be interspersed in anaplastic astrocytoma.
- Average survivial of patients with anaplastic astrocytoma is more than 2 years.
- Rare anaplastic astrocytomas are asscoaited with hereditary colonic polyposis or neurofibromatosis.

Pleomorphic Xanthoastrocytoma (PXA):
- It is a bizarre, supratentorial astrocytoma of young people that often invovles both leptomeninges and cerebral cortex.
- It shows fibrillary matrix with pleomorphic, hyaline lipid laden, giant cells and multinucleated cells, protein granular degenerations may be prominent.
- Intracellular lipid content is an important feature and empty round vacuoles are seen well in paraffin sections after GFAP staining.
- Astrocytes are often surrounded by reticulin fibres.

SEGA:
- The tumor arises from medial portion of the floor of lateral ventricle, where subependymal nodules of giant astrocytes called “Candle gutterings” are frequently found.
- It is associated with tuberous sclerosis.
- The tumor grow into lateral ventricle and may obstruct the foramen of monro.
- It is composed of giant astrocytes with large nuclei and prominent nucleoli.
- These giant astrocytes with thick cytoplasmic processes form disoriented fascicles.

EPENDYMOMA
- Ependymomas are glial neoplasms that occur almost exclusively adjacent to a ventricle in the cerebral hemispheres, in brain stem and in spinal cord.
- The WHO classification of ependymal neoplasm encompasses four groups.
  - Ependymoma and variants – WHO grade II
  - Anaplastic ependymoma – WHO grade III
  - Myxopapillary ependymoma – WHO grade I
  - Subependymoma – WHO grade I
- Most pediatric ependymal tumors are intracranial and arise in the posterior fossa.
- Multiple spinal cord ependymomas are typically associated with NF2.
- Supratentorial tumors affect both children and adults but are more common in adults.

- Gross:
  - Ependymomas are relatively well demarcated tumors with pushing borders with variable appearances.
  - The intraventricular tumors are usually soft and papillary more homogenous granular lesions arise in parenchyma.
  - Cystic degenerations and calcifications are common.

- Histology:
  - Tumor cells have well defined cytoplasm with tapering processes.
  - These may form small “rosette” like nests or remain attached to thin walled blood vessels.
  - Nuclear chromatin is distributed irregularly in delicate node producing salt and pepper or open pattern.
  - Nucleoli are inconspicuous, mitotic figures (<5/10HPF) are seen.
  - The characteristic feature of ependymomas is the polarized orientation of the tumor cells around blood vessels to form pseudorosettes.
  - The cellular processes form long tapering fibrillary processes or a dense fibrillary web.
  - Apart from these rosettes and epithelial structures, tumors are moderately cellular with compactly arranged cells and variable fibrillary matrix. Mild nuclear atypia and small foci of necrosis are also seen.
  - Immunohistochemistry:
    - GFAP, vimentin, EMA negative
    - Immunoreactive for S100, CD99, CD56.

GLIOMAS:
- Glioma is a term that include astrocytoma, glioblastoma, ependymoma and oligodendroglioma and their various subtype and combinations.
- The important general rule is gliomas tend to contain GFAP and lack collagen, reticulin and fibronectin in their parenchyma.
- Gliomas are difficult to distinguish from gliosis.
- Features that distinguish glioma cells from gliosis and normal parenchyma include pleomorphism, nuclear hyperchromasia, nuclear cluster formation, nuclear molding, mitoses and calcifications.
- Gliomas expand whereas gliosis contracts.
- Granular calcifications scattered among hypercellular glia favour glioma.
- Microcysts, calcifications and mitoses are important diagnostic features of gliomas.
- Nuclear pleomorphism and hyperchromasia is valuable in distinguishing margins of glioma.
- Away from the tumor epicenter, diffuse astrocytomas may show only rare cells with atypical nuclei, no definitive recognizable tumor.
- Rare gliomas produce diffuse and extensive involvement of the CNS called gliomatosis cerebri.

CRANIOPHARYNGIOMA:
- Craniopharyngiomas are histologically benign tumors thought to arise from “squamous epithelial rests” present from the tuber cinereum of pituitary gland presumably along the track of an incompletely involuted hypophyseal pharyngeal duct.
- They represent 1-2% of all intracranial neoplasms and 10% tumors of sellar region.
- They are more frequent in children and adolescents.
- They represent the most common non glial brain tumors.
- Most of them are suprasellar in location.
- They are typically solid and cystic lesions on neuroimaging with areas of calcification.
- They are of two variants
  - Adamantinomatous craniopharyngioma
  - Papillary craniopharyngioma

- Gross:
  - Mostly cystic, few are solid and some have both cystic and solid elements.
  - The adamantinomatous is mostly cystic where as papillary are solid lesions.
  - The cystic component of the tumor contains a viscous admixture of glistening birefringent cholesterol crystals and calcific desquamated debris that gives a characteristic “machinery oil” appearance.
  - The solid component has rubbery texture and may contain foci of calcium salts or even bone.
  - Papillary craniopharyngiomas rarely show calcification.

- Histology:
- Adamantinomatous craniopharyngioma:
  - Characterised by stratified epithelium with a palisading arrangement of basal cells, intermixed with nodular strands of solid and cystic epithelium.
  - The cystic areas are lined by simple stratified squamous epithelium supported by a collagenous basement membrane.
  - These secondary degenerations lead to formation of laminated masses of keratin that undergo calcification.
  - These nodular masses of keratin are k/a “wet keratin” and are distinctive and diagnostic of craniopharyngiomas.
  - Lamellar bone may be deposited in areas of calcification.
  - Extensive fibrosis, chronic inflammation and cholesterol clefts with giant cell reaction may be prominent.

- Papillary craniopharyngioma:
  - More discretely circumscribed and lack typical calcification and machinery oil cyst.
  - The tumor consists of well differentiated, squamous lined papillae, interrupted by prominent cores of fibrovascular stroma.
  - The squamous like epithelium lacks true keratin formation and keratohyaline granules, thereby differing from epidermoid and dermoid cysts.
  - Craniopharyngiomas are essentially benign tumors.
  - Mitotic figures and other features of histologic aggression aside from focal invasion are rarely seen.
  - Tumoral proliferation measured by MIB-I labelling index is ingeneral low

By-

PEDIATRIC TUMORS OF CENTRAL NERVOUS SYSTEM

Under the age of two years –

Choroid plexus papillomas

Anaplastic astrocytoma

Teratomas

First decade

Medulloblastomas

Astrocytoma

Ependymoma

Craniopharyngioma

Glioma

Metastases is rare, when they occur at this age metastases of a neuroblastoma are most frequent

Astrocytomas occur at any age, but glioblastoma multiforme is mostly seen in older people.

CHOROID PLEXUS PAPILLOMA:

The choroid plexus are a secretory organ responsible for the production of CSF, consists of richly vascularized fibrous stroma lined by an epithelium derived from neuroectodermal cells

Age : Most of these tumors appear in childhood

Site : They can occur in any portion of choroid plexus, but are more common in the lateral ventricles of children and fourth ventricle of adults

Tumors derived from the choroid plexus epithelium show considerable morphologic and biologic diversity

Majority of them are benign neoplasms that replicate the villous architecture of the parent organ and are termed Choroid plexus papillomas (WHO grade I).

Clinical and radiographic features include hydrocephalus

The tumor must be larger than normal choroid plexus to diagnose choroid plexus papilloma because its microscopic features are very similar to normal choroid plexus

Gross: Choroid plexus papilloma is a friable mass having villiform or bosselated surface, cystic lesions are exceptional.

Calcifications are common.

Microscopy: Complex array of branching fibrovascular fronds covered by a monolayer of uniform cuboidal/columnar epithelial cells with minimal nuclear atypia and little mitotic activity.

In contrast to the “cobblestone” pattern of normal choroid plexus, papillomas typically display taller epithelial cells which lack apical intercellular separations. These cells rests on basement membrane, apices are joined by functional complexes and crowned by microvilli, may be ciliated.

The stroma is infiltrated by foamy macrophages.

Few foci show metaplastic bone or cartilage formation.

The peculiar features is papilloma exhibiting overt neuronal differentiation signaled by micronodular collections of syn-rich matrix (choroid plexus papilloma with neuropil like islands).

Immunohistochemistry: Cytokeratin, transthyretine positive for choroid plexus epithelial cells. Some express GFAP and some express synaptophysin.

Differential diagnosis:

Papillary variant of ependymoma:

Papillary ependymoma occurs in different location than choroid plexus papilloma

Metastatic tumors including papillary variant of thyroid, breast, renal and ovarian carcinomas.

Papillary meningioma.

Mucin production, lack of whorls, lack of solid syncitial foci distinguish from papillary meningioma.

Atypical choroid plexus papilloma Grade-II:

It is an interface between papilloma and carcinoma.

Criteria is two or more mitotes/10 random HPF.

Choroid plexus carcinoma Grade-II:

Very rare neoplasm.

Consists of sheets of anaplastic cells with necrosis invasion, high proliferative activity.

Papillary features may be difficult to distinguish.

Primary carcinoma of choroid plexus closely resembles metastatic carcinoma so diagnosis should be made carefully.

Papillary structure breaks down and replaced by nests and Pattern less sheets of anaplastic cells with pleomorphism and mitotic activity.

TERATOMA:

CNS germ cell tumors arise from primordial germ cells that migrate to developing central neuraxis or as form native stem cell elements remains a speculative matter.

Age: They occur in first two decades of life.

Sex: Males are affected twice as frequently as females.

CNS germ cell tumors generally are sporadic but are recognized to complicate Kleinfelter syndrome and their incidence may be increased in setting of Down’s.

Suprasellar tumors produce visual field defects, Diabetes insipidus, and hypothalamopituitary failure. pineal region tumors produce obstructive hydrocephalus.

Teratomas contribute the majority of congenital CNS germ cell tumors.

This tumor group includes

mature teratoma

immature teratoma

Teratoma with malignant transformation.

Sarcomas of undifferentiated or rhabdomyosarcomatous aspect, leiomyosarcoma, adenocarcinoma of enteric type, squamous carcinoma and erythroleukemia have been reported to arise from intracranial teratoma containing germ cell tumors.

The spontaneous maturation of teratomas has been recorded.

The progressive, paradoxial enlargement of these mature neoplasm has been referred to as “The growing teratoma syndrome”.

Ki67/MIB-I assessment can demonstrate the levels of proliferative activity within the fully differentiated tissues of such recurrent lesions.

MEDULLOBLASTOMA (GRADE-IV):

The medulloblastoma is a common primitive neuroectodermal tumor that arises in the cerebellum or in the roof of fourth ventricle.

Age: It is most common in children but also in young adults rare in patients over 35 years.

It is often associated with ischromosome 17q.

Because it spreads along CSF, treatment should be directed at entire neuraxis.

About 5% medulloblastomas metastalize to systemic location particularly to bone.

Medulloblastoma is a small, round, blue cell tumor with marked hypercellularity, anaplastic nuclei and a high nuclear cytoplasmic ratio.

Its neuronal phenotype is demonstrated by positivity of neoplastic cells for synaptophysin.

Regardless of its other lines of differentiation, neuronal differentiation is a defining characteristic of medulloblastoma.

Regions of glial differentiation can be noted histologically and confirmed by GFAP.

Fibrillarity is extremely important to the diagnosis of medulloblastoma.

The fibrillar cellular processes arise directly from neoplastic cells in medulloblastoma.

Rosettes with cores filled with fibrils, Homer Wright rosettes in CNS are characteristic.

Differential diagnosis:

Small cell carcinoma and lymphoma – Lack fibrillarity.

Primary CNS lymphoma – Reactive fibrillar cells are seen, neoplastic cells do not have fibrillary process.

Variants:

Desmoplastic medulloblastoma (Grade IV):

They have both abundant reticulin and crowded proliferating cells and pale islands of tissue that lack reticulin and are less crowded with cells.

These islands show neuronal markers like synaptophysin and low proliferation.

These islands are called reticulin free zones and give nodular appearance.

They are also found around 3^rd ventricle, thalamus hypothalamus and neurohypophysis

The anaplastic astrocytoma, IDH mutant WHO grade III often evolves from a well differentiated precursor lesion showing CDKN2A/B genes deletion that encode P^16,P¹⁵, and P¹⁴.