childhood CNS tumors Ravi G - Dr.ravi gautam.pptx

childhood CNS tumors

1. CHILDHOOD BRAIN TUMORS RAVI GAUTAM MODERATOR- DR. ANITA P. JAWALGI 1

2. Anatomy Histology WHO classification Classification based on location and their clinical features Childhood Brain tumors Recent advances Algorithm Take home message 2

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4. HUMAN BRAIN central organ of the human nervous system. The brain consists of the cerebrum, the brainstem and the cerebellum. CEREBRUM Largest part of the brain, Ovoid shaped, 2 incompletely separated cerebral hemispheres. Corpus callosum , a connecting bond b/w two hemispheres lie at the bottom of fissure. Outer surface of hemisphere, covered with cortex, is highly folded by sulci and gyri . Core of hemisphere consists of white matter, containing a group of nuclei called basal ganglia. Cavity inside each hemisphere is called lateral ventricle. Cereberal hemisphere has three poles, three surfaces and three borders . Poles-1. Frontal pole. 2.Temporal pole. 3.Occipital pole. Surfaces – 1.Superolateral surface subdivided into frontal lobe, temporal lobe, parietal lobe and occipital lobe . 2.Medial surface- It includes sulci and gyri and corpus callosum. 3.Inferior surface Borders- 1. Superomedial border. 2. Inferolateral border. 3. Medial occipital and medial orbital border. 4

5. Fig- Brain 5

6. Fig-Lateral aspect of cerebral hemisphere 6

7. . BRAINSTEM Brainstem consists of midbrain, pons and medulla from above downwards. Superiorly brainstem (mid brain) is continuous with the structures forming forebrain- thalamus, hypothalamus and cerebral hemispheres. Inferiorly it is continuous with the spinal cord. Posteriorly, the pons and medulla are separated from cerebellum by the ventricle. MIDBRAIN Internal structure of mid brain is divided as tectum and cerebral peduncles . TECTUM The part lying behind the transverse line drawn through cerebral aqueduct is called tectum. It consists of superior and inferior colliculi of the two sides. CEREBRAL PEDUNCLES The part lying in front of the transverse line is made up of right and left halves called cerebral peduncles. Each peduncle consists of three parts – crux cerebri , substantia nigra and tegmentum . PONS The pons lies between the medulla oblongata and the midbrain. The pons is connected to the cerebellum by the cerebellar peduncles. The pons houses the respiratory  pneumotaxic center and  apneustic centers. MEDULLA OBLANGATA The medulla oblongata is the lower half of the brainstem, continuous with the spinal cord. Its upper part is continuous with the pons. The medulla contains the cardiac, respiratory, vomiting and vasomotor centres dealing with heart rate, breathing and blood pressure. 7

8. Fig-Ventral and dorsal views of brainstem 8

9. CEREBELLUM The cerebellum lies behind pons and medulla, in the posterior cranial fossa. It is separated from the cerebrum by a fold of duramater called as tentorium cerebelli . Like the cerebrum, the cerebellum has the superficial layer of grey matter, the cerebellar cortex. PARTS - Cerebellum consist of vermis and two lateral hemispheres . Two hemispheres are separated by a deep depression called the vallecula . FISSURES - Primary fissure, posterolateral fissure, horizontal fissure . Primary fissure runs transversely across the superior surface. Postero lateral fissure is seen on inferior aspect. Horizontal fissure divides the cerebellum into upper and lower halves. Primary and posterolateral fissure divides the cerebellum into three lobes- Anterior, Posterior and Flocculonodular lobe. Anterior lobe- lies anterior to primary fissure. Posterior lobe- lies b/w the two fissures. Flocculonodular lobe- present in the inferior surface of cerebellum. Anterior and posterior lobes together forms the corpus cerebelli. 9

10. Fig - Median saggital section through brainstem and cerebellum 10

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12. 12 Low-power LM of cerebral cortex. A richly vascularized leptomeninges (LM) invests the external surface of the cerebral cortex. The outermost cortical layer—a pale-stained zone called the molecular layer(ML) —contains chiefly nerve fibers. Deeper, ill-defined layers contain different types of neurons that make up the remaining cortical gray matter. Small blood vessels (arrows) from the pia mater penetrate the cerebral cortex substance Higher magnification LM of cerebral cortex. Pyramidal cells ( PC ) with apical dendrites are closely associated with smaller, round glial cells ( GC ). The surrounding neuropil is an interwoven meshwork of neuronal and glial cell processes. In routine H&E sections, the neuropil appears as a finely textured eosinophilic background, but neurites in the neuropil are not well resolved. LM ML PC GC

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14. 14 Gray matter and white matter: Gray matter contains abundant neuropil surrounding large neurons and smaller astrocytes and oligodendroglia (A). Neuropil is the term used for the fine amorphous eosinophilic background matrix of the CNS that fills the space between the cell bodies of the various cellular constituents as seen on H&E stains (B ). White matter, in contrast, is composed primarily of oligodendroglia and the axons that they myelinate, and displays a much more uniform, homogeneous appearance (C). A B C

15. 15 Neurons: Classical neuronal features, as illustrated by a motor neuron from the ventral horn of the spinal cord, include a large cell body (soma, perikaryon ) with abundant cytoplasmic Nissl substance (rough endoplasmic reticulum, the “ tigroid substance” of early microscopists ), cytoplasmic processes, and a large nucleus with a single prominent nucleolus (A). The large process extending to the right is clearly recognizable as a dendrite by its content of Nissl substance, whereas in this fortuitous section, the smaller process extending to the left is identified as the neuron’s axon by its lack of Nissl substance. Axons are further distinguished from dendrites by their non-tapering profile (B). The non-tapering profile of axons is easily recognized in white matter (C). The extremes of neuron size and shape are readily apparent rom a comparison of a large motor neuron (A) with the small granular cell neurons of the cerebellar cortex (D) that approximately the same size as a motor neuron’s nucleolus A B C D

16. 16 Oligodendroglia: As seen here in a white matter tract (the corpus callosum) cut in longitudinal section, these glia may be identified, even at low power, as rows of nuclei queuing up between fascicles of myelinated axons Oligodendroglia: In many specimens, oligodendroglia exhibit characteristic perinuclear halos. This “ fried egg” appearance is an artifact to hypoxia/ischemia and delayed fixation, and is a useful diagnostic feature that is also exhibited by oligodendrogliomas .

17. 17 Ependyma and the subependymal plate: The lining for the ventricular system varies from a robust ciliated-columnar epithelium to nearly squamous flattened cuboidal .

18. 18 Choroid plexus: Choroid plexus produces the cerebrospinal fluid and is found in the lateral ventricles , foramen of Monro , roof of the third ventricle, and fourth ventricle. Histologically, choroid plexus is seen to be covered by simple cuboidal epithelium (modified ependyma ); in adults, each choroid epithelial cell bears a single prominent paranuclear cytoplasmic vacuole.

19. 19 Central canal of the spinal cord: In the child (A), the central canal is widely patent and exhibits the ciliated columnar ependymal lining expected in a young individual. In contrast, the central canal of adults is typically obliterated over much of its length, with only residual small nests and occasional rosettes of few ependymal cells (B). A B

20. 20 Pineal histology: The pineal gland has a richly glandular architecture that is totally unlike any other region of the CNS. Salient features include a prominent lobular organization with connective tissue septa (A) and pineocytic rosettes (B). The latter impart a distinctly neuroendocrine character. A B

21. 21 Cerebellar cortex: The adult cerebellar cortex is composed of three layers—an outer hypocellular molecular layer, a middle Purkinje cell layer, and an inner densely populated granular cell layer. Whereas the Purkinje cells are prototypically neuronal in appearance, the small cells of the granular layer are hardly recognizable as neurons by traditional histologic criteria. A cross section on a cerebellar folium (A) shows the typical broadly branching Purkinje cell dendritic arbor. However, sections taken parallel to the folia (B) reveal the streamlined “on edge” appearance on the arbor, which should not be interpreted as pathologic pruning. The fetal cerebellum (C) has an additional cortical lamina, the external granular layer, applied to the surface of the cortex. This pool of cells populates the internal granular cell layer during development and is, thereby, depleted by the end of the first year of postnatal life A B C

22. WHO CLASSIFICATION OF CNS TUMORS Diffuse astrocytic and oligodendroglial tumours Diffuse astrocytoma,IDH -mutant Gemistocytic astrocytoma,IDH -mutant Diffuse astrocytoma,IDH-wildtype Diffuse astrocytoma,NOS   Anaplastic astrocytoma. IDH-mutant Anaplastic astrocytoma. IDH-Wildtype Anaplastic astrocytoma,NOS   Glioblastorna . IDH-wildtype Giant cell glioblastoma Gliosarcoma Epitheliod glioblastoma   Glioblastoma,IDH -mutant Glioblastoma,NOS   Diffuse midline glioma , H3K27M-mutant Oligodendroglioma . IDH-mutant and 1p/19q-codeleted Oligodendroglioma , NOS  Anaplastic oligodendroglioma . IDH-mutant and 1p/19q-codeleted Anaplastic oligodendroglioma,NOS   Oligoastrocytoma , NOS Anaplastic Oligoastrocytoma , NOS 22

23. Others astrocytic tumours Pilocytic astrocytoma Pilornyxoid astrocytoma Subepenclymal giant cell astrocytoma Pleomorphic xanthoastrocytoma Anaplastic pleomorphic xanthoastrocytoma Ependymal tumours Subependymoma Myxopapillary ependymoma Ependymoma Papillary ependymoma Clear cell ependymoma Tanycytic ependymoma Ependymoma,RELA fusion-positive Anaplastic Ependymoma   Other gliomas Chordoid glioma of the third ventricle Angiocentric glioma Astroblastroma   Choroid plexus tumours Choroid plexus papiloma Atypical choroid plexus papiloma Choroid plexus carcinoma Perineurioma Hybrid nerve sheath tumours Malignant peripheral nerve sheath tumour Epithelioid MPNST MPNST with perineurial differentiation Meningiomas Meningioma Meningothelial meningioma   Fibrous meningioma Transitional meningioma Psammomatous meningioma Angiomatous meningioma Microcystic meningioma Secretory meningioma Lymphoplasmacyte rich meningioma   Metaplastic meningioma Chordoid meningioma  Clear cell meningioma Atypical meningioma Papillary meningioma   Rhabdoid meningioma Anaplastic (malignant meningioma ) 23

24.   Mesenchymal/non meningiothelial tumours Solitary fibrous tumour / haemangiopericytoma Grade1  Grade2 Grade3 Haemangioblastoma Haemangioma Epithelioid haemangioendothelioma Angiosarcoma Kaposi sarcoma  Ewing sarcoma/ PNET Lipoma Angiolipoma Hibernoma Liposarcoma Desmoid type fibromatosis Myofibroblastoma Inflammatory myofibroblastic tumour Beningn fibrous histiocytoma Fibrosarcoma  Undifferentiated pleomorphic sarcoma/ malignant fibrous histiocytoma Leiomyoma Leiomyosarcoma Rhabdomyoma Rhabdomyosarcoma   Chondroma Chondrosarcoma Osteoma Neuronal and mixed neuronal- glial tumours Dysembryoplastic neuroepithelial tumour Gangliocytoma Ganglioglioma Anaplastic ganglioglioma Dysplastic cerebellar gangliocytoma ( Lhermitte-Duclos disease) Desmoplastic infantile astrocytoma and ganglioglioma Papillary glioneuronal tumour  Rosette-forming glioneuronal tumour Diffuse leptomeningeal glioneuronal tumour Central neurocytoma Extraventricular neurocytoma Cerebellar liponeurocytoma Paraganglioma 24

25. Tumours of the pineal region Pineocytoma Pineal parenchymal tumour of intermediate differentiation Pineoblastoma Papillary tumour of pineal region  Embryonal tumours Medulloblastomas,genetically defined Medulloblastomas,WNT Activated Medulloblastomas,SHH Activated and TP53-mutant Medulloblastomas,SHH Activated and TP53-wildtype Medulloblastomas,non -WNT/non-SHH Medulloblastomas,group 3 Medulloblastomas,group 4 Medulloblastomas , histologically defined Medulloblastomas , classic Medulloblastomas , desmoplastic /nodular Medulloblastomas , with extensive nodularity Medulloblastomas , large cell/ anaplastic Medulloblastomas , NOS  Embryonal tumour with multilayered rosettes C19MC altered Embryonal tumour with multilayered rosettes NOS Medulloepithelioma CNS neuroblastoma CNS ganglioneuroblastoma CNS embryonal tumour,NOS Atypical teratoid / rhabdoid tumour CNS embryonal tumuor with rhabdoid features Tumours of the cranial and paraspinal nerves Schwannoma Cellular Schwannoma Plexiform Schwannoma Osteochondroma Osteosarcoma Melanocytic tumours Meningeal melanocytosis Meningeal melanocytoma Meningeal melanoma Meningeal melanomatosis 25

26.   Lymphomas Diffuse large B-cell lymphoma of the CNS Immunodeficiency- associated CNS lymphomas AIDS related diffuse large B cell lymphoma EBV positive diffuse large B cell lymphoma, NOS Lymphomatoid granulomatosis Intravascular large B cell lymphoma  Low grade B cell lymphomas of the CNS T cell and NK/T cell lymphomas of the CNS Anaplastic large cell lymphoma, ALK positive Anaplastic large cell lymphoma, ALK negative MALT lymphoma of the dura Histiocytic tumours Langerhans cell histiocytosis Erdheim Chester disease Rosai Dorfman disease Juvenile xanthogranuloma Histiocytic sarcoma Germ cell tumours Germinoma Embryonal carcinoma Yolk sac tumour Choriocarcinoma Teratoma Mature teratoma Immature teratoma   Teratoma with malignant transformation Mixed germ cell tumour Tumours of the sellar region Craniopharyngioma Adamantinomatous craniopharyngioma Papillary craniopharyngioma Granulasr cell tumour of the sellar region Pituicytoma  Spindle cell oncocytoma Metastatic tumours 26

27. LOCATION Posterior fossa Supratentorial Intraparenchymal Sellar /Suprasellar Extra-axial 27

28. Posterior Fossa Tumors Brainstem-Glioma, Ganglioglioma, Astrocytoma Tectum / Cerebellum- Pilocytic astrocytoma, Medulloblastoma , Hemangioblastoma Fourth Ventricle- Medulloblastoma , Ependymoma , Choroid Plexus Papilloma CP Angle- Acoustic neuroma, Meningioma, Choroid plexus papilloma, Epidermoid Cyst 28

29. Supratentorial-Intraparenchymal Astrocytoma Ependymoma Desmoplastic Infantile Ganglioglioma (DIG) Dysembryoplastic neuroepithelial tumor (DNET) Teratoma Ganglioglioma/ Gangliocytoma Primitive Neuroectodermal Tumor (PNET) Atypical teratoid / rhabdoid tumors 29

30. Supratentorial : Sellar / Suprasellar Craniopharyngioma Astrocytoma Rathke cleft cyst Germ cell tumors Hypothalamic hamartoma Langerhans cell histioctyosis Pituitary adenoma 30

31. Supratentorial- Extra axial Choroid plexus papilloma /carcinoma Langerhans cell histiocytosis Epidermoid / Dermoid Arachnoid cyst Metastasis 31

32. AGE Brain tumours in infancy: Teratoma. CNS PNET Choroid plexus papilloma Anaplastic astrocytoma Supratentorial more common <2yrs infratentorial more common 4-10 yrs equally common after 10yrs age 32

33. SPECIAL CONSIDERATIONS ON GROSS MORPHOLOGY Neoplasms that often have cyst + nodule • Pilocytic astrocytoma • Ganglioglioma • Hemangioblastoma • Craniopharyngioma 33

34. Posterior Fossa Tumors—C/F Developemental delay Sleepiness Nausea and vomiting (area postrema ) Truncal or gait ataxia Head tilt Cranial nerve palsies Macrocrania 34

35. Common Presentations of Hypothalamic and Pituitary Lesions Hypopituitarism– craniopharyngioma Diabetes insipidus – LCH Precocious puberty– hamartoma of tuber cinereum , hypothalamic glioma Amenorrhea– pituitary adenoma, Rathke cleft cyst 35

36. GRADING Grade I and II ( low-grade ):The tumor grows slowly Rarely infiltrates into nearby tissues. Grade II can infiltrate into nearby tissues Can be cured by surgery   Grade III and IV ( high-grade ): The tumor grows quickly Likely to infiltrate into nearby tissue Grade IV tumors usually cannot be cured/removed by surgery 36

37. Pleomorphic xanthoastrocytoma Superficial cerebral tumor Bizzare supratentorial astrocytoma WHO grade II/III Age : children and young adults (average age <20 years) Sex: M = F antecedent history of seizures Site : Leptomeninges Cerebral cortex (temporal lobe) 37

38. Commonly cystic Moderately firmer Cellularity : moderate (usually) Pattern: interlacing bundles Morphology : may vary from plump polygonal cells without processes to more fusiform cells having hyperchromatic nuclei, within a variably fibrillated matrix. Important feature: Intracellular lipid content and empty round vacuoles (after GFAP staining) Astrocytes often surrounded by reticulin fibers 38

39. ( Reticulin+ve stroma) cohesiveness (striking feature), usually prominent with leptomeningeal involvement and prominent microvascular component Mitoses: may be present ( never abundant ) Clues to diagnosis: Fibrillarity and pleomorphic, hyaline, lipid-laden, giant cells, and multinucleated cells Lipidized astroglial tumor cells must be distinguished from lipidized glioblastoma. Biological behavior: Aggressive usually (when compared to pilocytic astrocytoma and SEGA) 39

40. 40 Pleomorphic xanthoastrocytomas have notably variable tumor cell geometry, ranging from spindle-shaped cells arranged in fascicles to more globoid, eosinophilic cells with atypical nuclei. Smear preparations of pleomorphic xanthoastrocytoma are characterized by significant pleomorphism. Note the admixture of polygonal, elongated, and fibrillated astrocytes. The remarkable cohesion of the tissue is readily evident during preparation of the smears.

41. Genetic mutations : absent (except in few recurrent tumors/ tumors having transformation to anaplastic forms- TP53 mutation and EGFR amplification). The Astroglial features of these tumors: may vary b/w initial and recurrent tumors. Ultrastructural study- basal lamina present b/w cells (both neoplastic astrocytes and subpial astrocytes having it). IHC: GFAP- Astroglial tumor cells. 41

42. Subependymal giant cell astrocytoma WHO grade I neoplasm Age: first 2 decades Site: Wall of lateral ventricle or III rd ventricle Most common CNS neoplasm associated with the tuberous sclerosis complex Long-standing history of seizures (cortical and white matter hamartomas) Pathogenesis: LOH in TSC2 gene 16p13 mutation in TSC1 gene 9q34 Macroscopy : circumscribed, nodular, solid multicystic with calcification Radiography: Candle gutterings 42

43. Histopathology Heterogeneous population of spindled fibrillated cells admixed with more polygonal cells with abundant cytoplasm arranged in a fibrillated matrix. Giant astrocytes with thick cytoplasmic processes - form disoriented fascicles. Large pyramidal cells with vesicular nuclei and prominent nucleoli (resembling ganglion cells), Chromatin- fine granular Some cellular pleomorphism Conspicuous microvasculature features: dilated vessels with hyalinized wall Mitoses: may be present, foci of occasional vascular endothelial proliferation and necrosis (not indicate anaplasia ) Ultrastructural features - neuronal differentiation, including microtubules, rare dense core granules 43

44. IHC : Mixed glioneuronal differentiation Astrocytes = GFAP, S-100 Neuronal component = neurofilament proteins, neuronal associated class III β- tubulin , and neuropeptides Differential diagnosis : Desmoplastic cerebral astrocytoma of infancy Gliofibroma PXA Monomorphous angiocentric glioma 44

45. 45 Cellular heterogeneity is typical for subependymal giant cell astrocytomas. Large pyramidal-like cells are admixed with spindle shaped and smaller fibrillated astrocytes(a). Note the ganglionic-like cells, sometimes binucleate with prominent nucleoli (b). a b

46. A 2 year female child presents with a mass arising from the IVth ventricle. On gross, it is well demarcated with soft cystic areas. MR imaging shows usually hypointense areas on T1 images. Histopathology shows both perivascular pseudo- rosettes and true rosettes. IHC shows positivity for GFAP , PTAH and Vimentin. Diagnosis? 46

47. Ependymoma WHO grade II 10% of brain tumors and 6% of intracranial gliomas . Age : in < 3 years- constitute 30 % of intracranial tumors in < 18 years- constitute 10-15 % of intracranial tumors Sex- M=F Site : Typically arise near ventricular system IV ventricle > Lateral ventricle > Aqueduct > Spinal cord Age dependent distribution:- Children & adolescents- IV ventricle Adults- Spinal cord & filum terminale 47

48. Spinal cord ependymomas - Most common gliomas in pts. with NF-2. Macroscopy : well-demarcated usually (Despite the circumscription, subarachnoid spread may be present, sp. with IVth ventricular ependymomas ) Soft cystic Papillary appearance of intraventricular tumors Areas of hemorrhage (as they are highly vascular tumor) calcification 48

49. Histopathology: monotonous population compactly arranged cells variably fibrillated matrix Nuclei-round to oval, with fine and irregularly distributed chromatin and relatively inconspicuous nucleoli Cytoplasm- well defined with long, tapering, fibrillated processes Characteristic and diagnostically useful finding ---- Perivascular pseudorosettes of ependymomas - have a fibrillar zone : at least two nuclear or three erythrocyte diameters wide around central vessels .They are more common than true rosette 49

50. With the majority of tumor vessels involved: a characteristic pattern of halos around vessels. True ependymal rosette- ependymal cells evenly spaced perpendicular to and forming a central lumen Degree of fibrillary intercellular matrix varies significantly among tumors Hyalinization of the tumor vessels common Nuclear atypia , mitoses and necrosis- may be present (without anaplastic transformation) 50

51. CT and MRI - similar features in ependymomas , regardless of their location High vascularity - variable enhancement with intravenous contrast Ultrastructure: Perivascular rosettes, cilia, basal bodies, and microvillous inclusions IHC: Cellular processes of pseudorosettes : GFAP, PTAH and Vimentin Microlumen - CD99 Some tumors (sp. Papillary subtype)- CK, EMA or both positivity Keartin AE1/AE3 D/d: Astrocytomas- coarse chromatin Choroid plexus papillomas (most significant finding to differentiate ependymomas from choroid plexus papillomas by fibrillary background) Prognosis: Age, location, extent of surgical resection, and histologic grade combined with Ki-67. 51

52. 52 The prominence of individual processes in the perivascular pseudo rosettes varies markedly between ependymomas . Note the uniformity of the round nuclei and the conspicuous cellular polarity with a fibrillary matrix of processes extending to the vessel walls. True ependymal rosettes, although rare, are diagnostic for ependymomas . Note the typically irregular distribution of chromatin in delicate nodes that produces an "open" pattern, in contrast to the coarse chromatin in other gliomas.

53. WHO classification : three variants of ependymoma : cellular, papillary and clear cell. All have same clinical behavior, but their recognition as ependymomas is important (to differentiate them from other gliomas ) Cellular ependymoma : prominent cellularity with few rosetting structures. Papillary variant : papillary and tubular structures (similar to choroid plexus papillomas ) Clear cell variant : round nuclei with perinuclear halos (resembling those seen in oligodendroglial cells) can be distinguished from oligodendroglioma by its prominent PTAH-positive fibrils and vimentin immunoreactivity . D/d: oligodendroglioma central neurocytoma Diagnostic indicators of all these ependymomas : tumor location, chromatin pattern, and fibrillary nature of intercellular matrix 53

54. Astroblastoma Astroblastoma Location Cerebral hemispheres ( Supratentorial ) Gross circumscribed gliomas Microscopy Uniform architecture of perivascular pseudorosette ( thick, broad, non tapering cytoplasmic processes) IHC GFAP, Vimentin, S-100 D/d Ependymomas Diffuse infiltrating astrocytomas 54

55. Polar spongioblastoma Polar spongioblastoma Location wall of the third or fourth ventricles Microscopy Unipolar or bipolar glial cells with delicate processes - arranged in parallel palisading patterns IHC PTAH positive fibrils (Cellular processes) 55

56. Gangliocytomas Gangliocytomas Location temporal lobes Gross well circumscribed Microscopy composed of neoplastic ganglion cells in a poorly cellular glial mesenchymal stroma. Silver impregnation technique abnormal neuritic processes. 56

57. Dysplastic gangliocytoma of the cerebellum Dysplastic gangliocytoma of the cerebellum Location cerebellum Microscopy abnormal ganglion cells with abnormally myelinated parallel fibers, reduction of the adjacent granular layer and demyelination of the cortical white matter MRI imaging the peculiar focal thickening of the cerebellar folia 57 Dyplastic gangliocytoma of cerebellum demonstrates ganglionic cells resembling Purkinje cells

58. Desmoplastic infantile gangliogliomas Desmoplastic infantile gangliogliomas Location Frontoparietal region Macroscopy relatively circumscribed Microscopy mixed population of heterogeneous glia and globoid neurons in a conspicuous stroma with variable collagen deposition IHC either neuronal or glial cytoskeletal markers in variable numbers 58 Desmoplastic infantile gangliogliomas are composed of a mixed population of heterogeneous glia and globoid neurons in a conspicuous stroma with variable collagen deposition

59. Desmoplastic infantile astrocytomas Desmoplastic infantile astrocytomas Location superficial regions of the frontoparietal lobes Macroscopy relatively circumscribed Microscopy abundant, often dense desmoplasia (hallmark feature) with glial cell population IHC either neuronal or glial cytoskeletal markers in variable numbers 59

60. Dysembryoplastic neuroepithelial tumor Dysembryoplastic neuroepithelial tumor Location temporal lobes Macroscopy characteristically multinodular Microscopy multinodular architecture ( histologic hallmark), "oligodendrocyte-like" cells ( pilocytic astrocytes), with neurons in a mucoid matrix IHC confirms the glioneuronal nature of these lesions 60 Dysembryoplastic neuroepithelial tumor. The mixed cellular elements are composed of oligodendrocytes, astrocytes and neurons in variable proportions; however, the oligodendrocytic component is most often predominant .

61. Ganglioglioma Ganglioglioma Location temporal lobes Macroscopy commonly showing cystic and calcified components, relatively firm Microscopy abnormal neuronal cells and astroglia , often enmeshed in either a fibrovascular stroma or a fibrillary matrix IHC calbindin , neuronal-associated cytoskeletal proteins 61 Smears of ganglioglioma readily demonstrate mixed astrocytic and ganglionic populations in a fibrillary stroma.

62. Central neurocytoma WHO grade II neoplasm rare intraventricular neuronal tumors favorable prognosis following surgical resection. young adults well-demarcated partially calcified masses projecting into the ventricles, typically in the region of the foramen of Monro ( intraventricular - majority arose in the lateral ventricles) Age : 6 to 52 years homogeneous tumor cell population 62

63. composed of a uniform population of cells with round to slightly lobulated nuclei and finely speckled chromatin in a conspicuously fibrillated matrix A delicate microvasculature forms a branching network in a pattern slightly reminiscent of oligodendrogliomas . Uniform cells, the finely fibrillated matrix, and the typical microvessels A consistent and characteristic feature of these tumors are anuclear islands composed of a dense fibrillary matrix necrosis – rare mitotic activity, nuclear pleomorphism and endothelial proliferation: absent 63

64. 64 (a, b) Smear preparations of a central neurocytoma show uniform cells with round nuclei and delicately dispersed chromatin. The cytoplasm of the cells is ill defined and the eosinophilic matrix is moderately fibrillary. The vascular component is invariably delicate. a b

65. 65 The appearance of central neurocytomas in tissue sections typically consists of homogeneous cell population partially delineated by mild proliferation of a delicate vascular stroma. Higher magnification of a routine preparation of central neurocytoma easily demonstrates the diffusely dispersed and delicate chromatin pattern in the uniform round nuclei. Anuclear zones with dense fibrillary cellular processes are common

66. IHC: synaptophysin and neuronal cytoskeletal proteins (confirms neuronal nature of the tumor ) NF- consistent with the mature neuronal phenotype of these tumors. A small number of neurocytomas show mitotic activity, nuclear atypia, endothelial proliferation and even microfoci of necrosis. Although these changes may be associated with a less favorable outcome, they are less well correlated with prognosis than in glial neoplasms Tumor recurrence following subtotal surgical resection Tumors with higher MIB-1 : higher recurrence rate. Tumors with high MIB-1 and/or vascular proliferation should be termed " atypical central neurocytoma ” Ultrastructural features: clear and dense core vesicles, cellular processes filled with parallel microtubular arrays, and synapses (definitively confirm the diagnosis) 66

67. Pineoblastoma Most primitive pineal neoplasm 3-17% of pineal region tumors in children. first decade of life M>F (2:1) poorly defined Cut section: gelatinous and hemorrhagic Necrosis – common, calcification - variably observed Neuroimaging - poor delineation between tumor and brain Locally infiltrative growth is often accompanied by perifocal edema 67 Pineoblastoma . Note the densely cellular, compact arrangements of the primitive cells forming ill-defined arrangements which tend to resemble the primitive rosettes in medulloblastoma (center)

68. Highly cellular composed of small, pleomorphic cells that contain round to oval nuclei with coarse, hyperchromatic chromatin The cells are typically arranged in patternless sheets but may form Homer Wright rosettes Retinoblastomatous differentiation, with Flexner- Wintersteiner rosettes and fleurettes . The ultrastructural features : consistent with a poorly differentiated neuroepithelial neoplasm. Early photosensory phenotypic expression: characterized by polarization of cytoplasmic organelles, cilia, annulate lamellae and well-developed smooth endoplasmic reticulum, may be present 68

69. Embryonal tumors Primitive, clinically aggressive neoplasms first decade of life. All embryonal tumors, regardless of histogenesis , share the common features of high cellularity , numerous mitoses, and at least focal necrosis. These features reflect the clinically aggressive behavior that corresponds to a grade IV tumor. Common propensity for leptomeningeal invasion arise from transformation of undifferentiated and immature neuroepithelial cells Diverse cell populations in the immature nervous system - vulnerable targets for neoplastic transformation 69

70. The current classification scheme recognizes a number of embryonal tumors with restricted and relatively defined histogenetic potentials along neuronal, ependymal , and retinal cell lineages: the cerebral neuroblastoma , ependymoblastoma , and retinoblastoma, respectively. A very rare embryonal neoplasm which also merits separate identification is the medulloepithelioma . In contrast to the other tumors mentioned, this neoplasm has the greatest potential for expressing divergent neural cell types The designation primitive neuroectodermal tumor (PNET) embraces the concept that such tumors arise from primitive neuroepithelial progenitor cells that are equivalent throughout the neuraxis . Accordingly, these tumors would have similar histopathologic features and biologic behaviors. Currently, the use of PNET for diagnostic classification is limited to medulloblastomas and to neoplasms that are located at other sites of the neuraxis but are indistinguishable from medulloblastomas . Analogous progenitor cells exist in selective regions of the immature human brain, their transformation would most likely result in PNET phenotypes. 70

71. Medulloepithelioma Medulloepithelioma Location cerebral hemispheres Microscopy mitotically active, pseudostratified columnar epithelium, often arranged in ribbons of tubules or papillary rosettes, with variable interposition of delicate stromal elements IHC abundant vimentin, insulin-like growth factor I, and basic fibroblastic growth factor in this primitive epithelium 71 The hallmark feature of medulloepitheliomas is the columnar, often pseudostratified, epithelium arranged in papillary and tubular formations. Note the internal and external limiting membranes of the epithelium. Note the resemblance to the primitive neuroepithelium of the embryonal neural tube.

72. Cerebral neuroblastoma Cerebral neuroblastoma Location Supratentorial Macroscopy massive, and multicystic Microscopy neuroblastic (Homer Wright) rosettes, small cells with poorly defined cytoplasm, round to ovoid nuclei and hyperchromatic nuclei, slightly fibrillated matrix, IHC PTAH staining and GFAP (confirm the absence of a neoplastic glial component) 72 Low magnification view of a neuroblastoma commonly shows small cells arranged in highly cellular clusters and variably delineated Homer Wright ( neuroblastic ) rosettes

73. Ependymoblastoma Ependymoblastoma Location supratentorial Microscopy high cellularity with poorly differentiated small cells forming either amorphous arrangements or the characteristic rosettes and tubules chemistry IHC GFAP variably present within the amorphous groups of primitive polygonal cells and in occasional cells within the ependymal rosettes and tubules. D/d anaplastic ependymomas 73

74. Retinoblastoma Most common intraocular tumors of childhood the only embryonal tumor for which the genetic basis of neoplastic transformation is known. The transforming event occurs in the immature retina when both alleles of the RB-l tumor suppressor gene are inactivated within a single cell. composed mostly of amorphous sheets of poorly differentiated small cells, but the majority of retinoblastomas display, at least in areas, different proportions of Flexner- Wintersteiner and Homer Wright rosettes IHC: neuronal/ photoreceptor-associated proteins GFAP - reactive "stromal" astrocytes " retinocytomas " (numerous fleurettes and low cellularity) immature retinal neural epithelium 74 Flexner- Wintersteiner rosettes, if present, are one of t he diagnostic histopathologic features of retinoblastoma

75. A 8 year male child present with cerebellar midline mass. On Gross : soft, friable with necrotic areas. It causes drop metastases in lumbar CSF. On CT scan- hyperdense areas. T2 MRI: overall iso - hyperdense aeas . MR spectroscopy- elevated choline levels. IHC showing positivity for: class III-tubulin, neurofilament epitopes Diagnosis? Fig. Axial non contrast CT scan 75 Densely cellular tumor composed of closely packed primitive cells along with rosettes

76. Medulloblastoma Most common of the embryonal tumors. one quarter of all intracranial tumors. end of the first decade (peak incidence) M>F cerebellar midline (majority) The soft, often friable, tumors are macroscopically distinct from the adjacent brain. Necrosis is an invariable feature (punctate foci or more expansive zones) The lobular or desmoplastic variants (laterally in the cerebellar hemispheres)- well demarcated and have a markedly firmer consistency intensely cellular and composed of relatively small cells with scant cytoplasm and ill-defined cell borders. Mitoses are readily observed. Cause drop metastases in lumbar CSF 76

77. 77 Medulloblastomas are densely cellular tumors composed of closely packed primitive cells (a). The areas of high cellularity are frequently admixed with less cellular zones populated by cells showing variable formation of poorly defined processes (b). a b

78. nuclei – hyperchromatic, angular to ovoid shape with irregular membrane In addition to rosettes, the areas of neuroblastic differentiation, have an intercellular matrix composed of delicately fibrillated processes and cells with more pale and vesicular nuclei. IHC: class III-tubulin, neurofilament epitopes Desmoplastic variant of medulloblastoma (10-12% of cases): distinctive for a biphasic architecture with a follicular arrangement of tumor cells. Highly cellular sheets and trabeculae of typical tumor cells encompass islands characterized by lower cellularity and cells with finely fibrillated processes. The reticulin -free islands prominently demonstrate neuronal tubulin and neurofilament immunoreactivity . It is interesting to note that the characteristic nodular architectural pattern of the desmoplastic variant may not be present in the recurrent tumor specimen. 78

79. A third and most infrequent cytoarchitectural variant of medulloblastoma is the large cell medulloblastoma . This variant has an exceptionally aggressive biologic behavior and is characterized by polygonal tumor cells with large round or lobated nuclei with prominent nucleoli and relatively more abundant cytoplasm than in the more common tumors. Abundant mitoses and nuclear molding are typical, as are conspicuous areas of necrosis. Other rare variants of medulloblastoma include tumors showing striated muscle cell differentiation ( medullomyoblastoma ) with populations of more primitive cells that recall rhabdomyosarcoma , tumors showing marked nodularity ,and tumors showing lipid accumulation (" medullocytoma ”). The latter two types are associated with a better prognosis. 79

80. Atypical teratoid / rhabdoid tumor rare childhood brain tumors distinctive for the presence of " rhabdoid cells". posterior fossa (most common) ≤3 years of age male predominance. The large and polygonal rhabdoid cells are characterized by eosinophilic cytoplasm containing spherical fibrillary intracytoplasmic inclusions, and by vesicular nuclei with prominent large nucleoli. The rhabdoid cells may be abundant or may be incorporated into this complex mixture of primitive neuroepithelial cells, creating the impression of a composite tumor with features of a medulloblastoma , elements of mesenchymal spindle cells, and diverse epithelial elements. They are immunonegative with desmin , and may show variable immunopositivity with EMA, vimentin and smooth muscle actin. monosomy of chromosome 22 that distinguish these tumors from the medulloblastoma . extremely aggressive neoplasms 80

81. Solitary fibrous tumor Solitary fibrous tumor Location cerebrum, the lateral ventricle, the tentorium, the cerebellopontine angle, and the suprasellar cistern Macroscopy Although unencapsulated , typically have a well-defined "expansile" interface Microscopy moderately cellular, monomorphous groups of undulating spindle shaped cells arranged in a pattern less fashion or poorly formed fascicles with abundant band-like deposition of hyaline collagen fibers and prominent vascularity IHC CD34, Vimentin D/d fibroblastic meningiomas 81 Solitary fibrous tumor.Spindle cells arranged in poorly formed fascicles are intermixed with dense collagenous bands

82. Meningioma derived from the arachnoidal cells present in the arachnoidal villi and granulations, and in the stroma of perivascular spaces and choroid plexus. 13-19% of intracranial tumors and represent one-quarter of intraspinal tumors. only rarely during childhood. Epidural tumors (pediatric cases) - male predominance. Multiple meningiomas - in a/w central form of neurofibromatosis Pediatric tumors are more likely to demonstrate malignant transformation and have a higher proportion of the papillary variant. Loss of heterozygosity for loci on chromosome 22 Meningiomas can occur anywhere in the meninges (intracranial: sagittal area along the superior longitudinal sinus) 82

83. Intraventricular meningiomas arise presumably from arachnoidal cells within the tela choroidea or stroma of the choroid plexus. The left lateral ventricle is the most frequent location In the posterior fossa, the cerebellopontine angle over the petrous bone is a common site. In the spinal canal: thoracic > cervical > lumbar region. Most meningiomas are well-demarcated, globular masses with a thin capsule The tumors grow slowly compressing the brain and eroding into adjacent structures. The character of the cut surfaces is highly variable, often reflecting the predominant histologic variant, such as a gritty texture with abundant psammoma bodies or a more lipidic quality with the secretory type. 83

84. Neuroimaging studies are important complements to the histopathologic diagnosis of meningiomas Angiography often displays a characteristic tumor blush MRI may also be useful in partially discriminating the predominant histologic pattern of the tumor, especially on T2 weighted images where the syncytial and angiomatous components are hyperintense compared to fibroblastic variants. Numerous variants of meningiomas have been described reflecting the mesenchymal and epithelial histogenetic potential of arachnoidal cells. Although the majority of these variants exhibit similar biologic behavior, some are associated with systemic diseases, such as Castleman's disease with the chordoid variant and polyclonal gammopathies with lymphoplasmacyte -rich tumors. Meningotheliomatous ( syncytial ) and transitional meningiomas may exhibit the most typical " meningothelial " appearance of these tumors, characterized by groups of cells with poorly defined cell borders forming characteristic whorls around vessels or stromal elements and the presence of psammoma bodies. The cells contain nuclei with finely distributed chromatin and inconspicuous nucleoli. 84

85. Cytoplasmic inclusions within the nucleus result in the commonly described nuclear "vacuolization". The fibrous (fibroblastic), angiomatous and metaplastic forms comprise the " mesenchymal " variants They possess a variable degree of reticulin and are collagen rich The "epithelial" phenotype of meningiomas is expressed by the microcystic , secretory , clear cell (glycogen-rich), chordoid , and papillary variants PAS positive inclusions are commonly found in the secretory variant Both clear cell and chordoid variants behave in a more aggressive fashion All three types of meningiomas are considered, accordingly, as WHO grade II neoplasms . Clear cell meningiomas are glycogen rich, often located in the posterior fossa or spine, and behave in an aggressive manner Chordoid meningiomas , which interestingly appear to have a specific karyotype , contain areas that recall the histologic pattern of chordomas with ribbons of eosinophilic , vacuolated cells in a myxoid matrix. 85

86. 86 Meningioma. A smear preparation shows typical meningothelial cells with ill-defined cytoplasmic borders. The nuclei have very pale, powdery chromatin with conspicuous chromatin. Whorl formation is prominent in this case. The typical meningothelial whorl pattern in a tissue section of a transitional meningioma The clear cell variant of meningioma is composed of cells that are densely filled with glycogen. Note the characteristic meningothelial chromatin pattern

87. 87 Microcystic meningioma is composed of an admixture of syncytial/meningothelial patterns with microcystic zones In the angiomatous meningioma, hyalinized blood vessels are admixed with small nests of meningothelial cells in syncytial arrangements. Careful inspection of this variant may be necessary to document the meningothelial nature of these tumors

88. 88 Polygonal cells with well-defined cytoplasmic borders and eosinophilic inclusions typically compose secretory meningiomas. Smear preparations of atypical meningiomas show the characteristic meningothelial chromatin pattern of meningiomas Note the mitotic figure and increased cellular pleomorphism .

89. 89 Increased cellularity with loss of cytoarchitectural patterns, nuclear pleomorphism with prominent nucleoli, and microscopic necrosis are histopathologic features of atypical meningiomas. Note only a partial preservation of the syncytial pattern in this densely cellular field (a). Bizarre nuclear pleomorphism alone does not indicate anaplasia but is a frequent finding in atypical meningiomas (b) Cytogenetic analysis commonly shows abnormal profiles. Focal papillary patterns in densely cellular fields may be present in anaplastic meningiomas a b

90. Meningiomas also exhibit immunohistochemical features that are consistent with the dual mesenchymal and epithelial nature of the progenitor cells. The principal intermediate filament, present in almost 100% of cases, vimentin . Immunoreactivity for S-100 protein is variable and present in about 50% of cases, mainly in the fibroblastic areas. GFAP is consistently negative. 90

91. Papillary meningioma Microscopy highly cellularity, papillary structures around blood vessels, epithelial like cells with cuboidal/columnar shape and well defined cytoplasmic borders IHC PTAH-positive processes and fibrils ( perivascular cells) 91 Papillary meningiomas exhibit cuboidal to columnar cells arranged in pseudopapillae . This category of meningioma should be considered to be invariably malignant.

92. 1. Germinoma 2. Embryonal carcinoma 3. Yolk sac tumor (endodermal sinus tumor) 4. Choriocarcinoma 5. Teratoma Variants: mature, immature, malignant 6. Mixed germ cell tumors Primary intracranial germ cell tumors are rare occur primarily during childhood and adolescence. pineal and sellar regions, third ventricle and hypothalamus, and only rarely in the spinal cord 92

93. Germinoma most frequent germ cell tumor arising in the neuraxis pineal and sellar regions (majority). M>F soft, friable masses with ill-defined borders. Cystic change and calcifications are common. Histopathologic features are similar to the gonadal counterparts, i.e. groups of polygonal cells with large, vesicular nuclei with prominent nucleoli intersected by a fibrovascular stroma infiltrated by small lymphocytes Mitotic figures are very frequent. extremely radiosensitive- favourable prognosis 93 Intracranial germinomas present the same histopathologic features as gonadal and other extragonadal counterparts. The large cells with prominent vesicular nuclei are delineated into groups by a stroma rich in lymphocytes

94. Embryonal carcinoma and yolk sac tumor ( endodermal sinus tumor) Embryonal carcinomas and yolk sac tumors are the most primitive of the germ cell tumors and most frequently present as one of the components of mixed germ cell tumors. Although embryonal carcinomas are less differentiated than the yolk sac tumor, the distinction between the two is ill defined and controversial. The incidence of these tumors is low M>F The yolk sac component is characterized by cuboidal/ columnar epithelial cells arranged in tubules and papillary structures, supported by a delicate connective stroma with capillary-sized vessels. Typical Schiller-Duval bodies and PAS-positive globules are usually present. The embryonal carcinomas are less differentiated and consist of patternless sheets of cells with large, vesicular nuclei and prominent nucleoli Immunoreactivity for α -fetoprotein can be demonstrated in both tumors syncytiotrophoblastic differentiation with the presence of multinucleate giant cells [β- hCG immunoreactive cells can also be found in these tumors] 94

95. 95 Embryonal carcinoma. Sheet-like growth of anaplastic malignant germ cells. Glands and syncytiotrophoblastic giant cell were present elsewhere in the tumor. Yolk sac tumor. Endodermal sinus pattern with a Schiller-Duval body in the center of the field. A Schiller-Duval body is a papillary structure that grows into a cystic space. The papilla is lined by tumor cells and has a central capillary

96. Choriocarcinoma Pure choriocarcinomas are extremely rare in the neuraxis well demarcated and typically hemorrhagic. Histologically , choriocarcinoma is characterized by a combination of syncytiotrophoblastic and cytotrophoblastic elements disposed in a bilayer pattern, surrounded by sinusoidal vessels. The syncytiotrophoblasts are strongly immunoreactive for β- hCG . 96 .

97. Teratoma composed of a mixture of tissues derived from all three germinal layers. constitute about 0.5% of all intracranial tumors M>F pineal region The mature forms are composed of well-differentiated, "adult-type“ ectodermal , mesodermal , and endodermal elements, the first including neuroectodermal elements. In the immature forms, any or all of the three germinal layer tissues is composed of more primitive elements resembling immature embryonic tissues. The malignant variant shows malignant transformation of one or more of the three adult tissues In the immature teratoma , the immature component is quite often composed of neuroepithelial elements, including patterns typical of medulloepithelioma , neuroblastoma , retinoblastoma,or ependymoblastoma 97 Benign teratoma measuring 9 cm and filled with mucin-containing endodermal-lined cysts . Tissues present included skin, bone, an neuroectodermally derived pigmented epithelium . No malignant component was identified.

98. Craniopharyngioma Craniopharyngioma Location Intrasellar and Suprasellar areas Macroscopy Both solid and cystic Microscopy Two variants : Adamantinomatous : Papillary ADAMANTINOMATOUS PATTERN : Characterized by stratified epithelium with a palisading arrangement of the basal cells, keratin formation, and microcystic changes. Papillary areas : Composed of simple stratified squamous epithelium resting upon a connective tissue stroma, usually forming pseudopapillary structures. 98 Histologic sections commonly demonstrate areas resembling the adamantinomatous pattern in addition to more dense palisades of basaloid cells forming irregular nests and trabeculae

99. RECENT ADVANCES INCIDENCE Childhood CNS tumor incidence varies by country from 1.12–5.14 cases per 100,000 persons with the highest incidence in the U.S.. CBTs are more common in males, though this varies by histologic type. In the U.S., Whites and Asians-Pacific Islanders have a higher CBT incidence than Blacks and American Indians/Alaska Natives, while Non-Hispanics have higher incidence than Hispanics. EPIDEMIOLOGY The most common brain tumor in children is medulloblastoma , which accounts for 10-20% of childhood brain tumors and 40% of tumors in the posterior fossa . Most brain tumors, chiefly medulloblastomas and glial tumors, involve the posterior fossa after the first 2 years of life. Most CNS tumors are glial tumors, which are classified by their location as supratentorial , cerebellar , or brainstem. Supratentorial astrocytomas comprise 30-40% of cases, with cerebellar astrocytomas and brainstem gliomas (15% each) comprising the remainder of the glial tumors. Unique variants in each of these groups have strong prognostic significance. For example, patients with exophytic gliomas do extremely well, whereas individuals with diffuse infiltrative tumors do poorly. Various genetic syndromes predispose pro bands to brain tumors, including neurofibromatosis, LiFraumeni syndrome, and tuberous sclerosis. Environmental exposure and immunosuppression are also associated with increased risk, including radiation ( gliomas ) and HIV (lymphoma). 99

100. . RISK FACTORS FOR CHILDHOOD BRAIN TUMORS 100

101. . EXPOSURE STRONG Cancer syndromes- NF1, NF2, Tuberous sclerosis, Nevoid Basal Cell Carcinoma. Ionizing radiation- therapeutic SOME/SUGGESTIVE Parental age- astrocytoma Birth defects Fetal growth- High birth weight Ionizing radiation- CT scan Folic acid/prenatal vitamins WEAK/INSUFFICIENT Maternal genetics Allergic condition - asthma Maternal medication- antihypertensive, antiemetics , analgesic. Parental occupational exposure- pesticide exposure 101

102. CNS TUMOR T/T Recent researches show that apart from standard treatment there are new treatments for Childhood CNS tumors which include high dose of chemotherapy with stem cell transplant. Standard treatment : Surgery Used to diagnose and treat childhood brain and spinal cord tumors Radiation therapy High-energy x-rays or other types of radiation kill cancer cells or keep them from growing. External radiation therapy - A machine outside the body sends radiation toward the cancer. Internal radiation therapy - A radioactive substance sealed in needles, seeds, wires, or catheters, placed directly into or near the cancer. External radiation therapy is used to treat childhood brain and spinal cord tumors . Chemotherapy Drugs are used to stop the growth of cancer cells, either by killing the cells or by stopping them from dividing. Systemic chemotherapy - When chemotherapy is taken by mouth or injected into a vein or muscle, the drugs enter the bloodstream and can reach cancer cells throughout the body. Regional chemotherapy -When chemotherapy is placed directly in the cerebrospinal fluid, an organ, or a body cavity such as the abdomen, the drugs mainly affect cancer cells in those areas. Intrathecal chemotherapy -Anticancer drugs given by mouth or vein to treat brain and spinal cord tumors cannot cross the blood-brain barrier and enter the fluid that surrounds the brain and spinal cord. Instead, an anticancer drug is injected into the fluid-filled space to kill cancer cells there. New types of treatment High-dose chemotherapy with stem cell transplant It is a way of giving high doses of chemotherapy and replacing blood -forming cells destroyed by the cancer treatment. Stem cells (immature blood cells) are removed from the blood or bone marrow of the patient or a donor and are frozen and stored. After the chemotherapy is completed, the stored stem cells are thawed and given back to the patient through an infusion. These re infused stem cells grow into (and restore) the body’s blood cells. 102

103. ALGORITHM 103

104. TAKE HOME MESSAGE Pediatric CNS tumors remain an underreported segment of the population with cancer because only one half are referred to speciality centers. Most pediatric brain tumors occur in the first decade of life . Most CNS tumors are glial tumors, which are classified by their location as supratentorial , cerebellar, or brainstem Unique variants in each of these groups have strong prognostic significance. For example, patients with exophytic gliomas do extremely well, whereas individuals with diffuse infiltrative tumors do poorly. Location determines nature than the tumor itself. Morbidity is clearly the greatest problem in patients with brain tumors because many of these tumors are in locations that are difficult to treat. Infratentorial tumors in childhood Primary tumors  infiltrative Metastasis  well-demarcated A priority area for future CBT epidemiological research is the elucidation of both common and rare genetic risk variants that modify risk. Age, location, genetic mechanisms, gross features, IHC and radiography: all have to be correlated with the microscopic pathologic findings. 104

105. References 1. Fletcher D. M. C. Diagnostic Histopathology of Tumors. In: Tumors of the central nervous system, 3ed. Elsevier;2007.p1653-1721. 2. Mills E. S., Greenson K. J,Hornick L. J,Longacre A. T,Reuter E. V. Sternberg’s Diagnostic Surgical Pathology. In: Brain, Spinal cord and Meninges, 6ed. Wolters Kluwer;2015.p385-485. 3. Weidner,Cote , Suster,Weiss . Modern Surgical Pathology. In: Central Nervous System Tumors, 2ed. Elsevier;2009.p1984-2027. 4. Childhood Brain and Spinal Cord Tumors Treatment Overview. Patient Version National Cancer Institute [Internet]2017 Feb 8.Available from: https://www.cancer.gov/types/brain/patient/childbraintreatmentpdq#section/_68. 5. Kupfer GM. Childhood cancer epidemiology. Medscape.2015 Sep;24:1-18. 6. Johnson KJ, Cullen J, Barnholtz -Sloan JS, Ostrom QT, langer CE, Turner MC et al.Childhood Brain Tumor Epidemiology: A Brain Tumor Epidemiology Consortium Review. NIH Public Access. 2014 December ; 23(12): 2716–2736. 8. Drake RL, Vogl AW, Mitchell AWM. Gray’s anatomy for students. Brainstem- Gross anatomy and internal structure, 3ed. Elsevier;2015.p 356-358 . 9. Drake RL, Vogl AW, Mitchell AWM. Gray’s anatomy for students. Cerebellum- Gross anatomy and internal structure, 3ed. Elsevier;2015.p 393-394 . 10. Drake RL, Vogl AW, Mitchell AWM. Gray’s anatomy for students. Cerebrum, thalamus and hypothalamus- Gross anatomy and internal structure , 3ed. Elsevier;2015.p 402- 405 . 11. Ovalle K. W, Nahirney C.P. Netter’s Essential Histology In: Nervous tissue, 2ed. Elsevier;2013.p117-122. 12. Mills E. S. Histology f or Pathologists In: Central Nervous System, 4ed . L ippincott williams & wilkins;2012.p301-332. 13. Walker D, Perilongo G , Punt J, Taylor R Brain and Spinal Tumors of Childhood In: Neuropsychological Outcome, CRC Press;2004.p214. 105

106. POST TEST (Total duration= 8.5 minutes) Q1 . Subependymal giant cell astrocytoma is the most common brain tumor associated with tuberous sclerosis complex. True/False (1 mark ) (30 seconds) Q2 . Name any 4 sites of primary CNS germ cell tumors (2 marks ) (1.5 minute) Q3. Name the tumors resembling oligodendroglioma (1 mark ) (1 minute) Q4. What is Neuropil (1 mark) (1 minute) Q5. Which of the following hereditary conditions does not predispose to CNS tumors ? (1 mark) (1 minute) a. NF- 1 and 2 b. Tuberous sclerosis c. Von Hippel Lindau syndrome d. Xeroderma pigmentosum 106

107. Q6 . A 5 year old child comes with supratentorial tumor, which is circumscribed and positive for GFAP, Vimentin and S-100. Describe the microscopic features, diagnose and give differential diagnosis (1+1+1= 3 marks) (2 minutes) Q7 . A 6 year old boy had been complaining of headache, ignoring to see the objects on the sides since 4 months of age. On examination, he was not found to be mentally retarded. His grades at school were good, but his visual acquity was diminished in both eyes. Visual charting showed significant field defect. CT scan of the head showed suprasellar mass with calcification. What is the most likely diagnosis in the case of this patient? Describe the histomorphological features in the figure. (2 marks) (1.5 minutes) 107

108. Q1. SEGA is the most common brain tumor associated with tuberous sclerosis complex. True/False (1 mark) Ans True Q2. Name any 4 sites of primary CNS germ cell tumors (2 marks) Ans. Pinealgland , suprasellar region, basal ganglia, thalamus, cerebral hemispheres, posterior fossa, spinal cord Q3. Name the tumors resembling oligodendroglioma (1 mark) Ans. Dysembryoplastic Neuroepithelial Tumor Low grade oligoastrocytoma (Low grade mixed glioma ) Q4. What is Neuropil (1 mark) Ans. Fine amorphous eosinophilic background matrix of the CNS that fills the space between the cell bodies of the various cellular constituents Q5. Which of the following hereditary conditions does not predispose to CNS tumors ? (1 mark) a. NF- 1 and 2 b. Tuberous sclerosis c. Von Hippel Lindau syndrome d. Xeroderma pigmentosum Ans. Xeroderma pigmentosum 108

109. Q6 . A 5 year old child comes with supratentorial tumor, which is circumscribed and positive for GFAP, Vimentin and S-100. Describe the microscopic features, diagnose and give differential diagnosis (1+1+1= 3 marks) Ans. Uniform architecture of perivascular pseudorosette ( thick, broad, non tapering cytoplasmic processes) Diagnosis: Astroblastoma Differential diagnosis: Ependymomas , Diffuse infiltrating astrocytomas Q7 . A 6 year old boy had been complaining of headache, ignoring to see the objects on the sides since 4 months of age. On examination, he was not found to be mentally retarded. His grades at school were good, but his visual acquity was diminished in both eyes. Visual charting showed significant field defect. CT scan of the head showed suprasellar mass with calcification. What is the most likely diagnosis in the case of this patient? Describe the histomorphological features in the figure . (2 marks ) Ans . Craniopharyngioma Histologic section commonly demonstrating areas resembling the adamantinomatous pattern in addition to more dense palisades of basaloid cells forming irregular nests and trabeculae 109