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Home , Subependymoma

Neuropathology 101 Dr David Wong Anatomical pathology

Goals

• CNS tumour classification • Pre/Intraoperative differential diagnosis • • Some practical molecular classification of diffuse gliomas. Neuropathology at Mater

• Diagnostic neurosurgical biopsies

• Perinatal autopsies • Adult autopsies WHO 2007 CNS tumour classification schemes 1. Cell of origin 2. Tumour grading 3. Molecular markers

WHO classification of CNS tumours 1/2 Astrocytic tumours Neuronal and mixed neuronal-glial Pilocytic WHO gr I tumours Pilomyxoid astrocytoma WHO gr II and gangliocytoma WHO gr I Subependymal giant cell astrocytoma WHO gr I Anaplastic ganglioglioma WHO gr III (SEGA) Desmoplastic infantile astrocytoma Pleomorphic xanthoastrocytoma (PXA) WHO gr II and ganglioglioma WHO gr I Diffuse astrocytoma WHO gr II Dysembryoplastic neuroepithelial tumour WHO gr III (DNET) WHO gr I WHO gr IV Central and Giant cell glioblastoma extraventricular neurocytoma WHO gr II Cerebellar liponeurocytoma WHO gr II Papillary glioneuronal tumour WHO gr I (spinal) WHO gr I Oligodendroglial tumours WHO gr II tumours Anaplastic oligodendroglioma WHO gr III Tumours of the pineal region Mixed glial tumours Pineocytoma WHO gr I WHO gr II Pineal parenchymal tumour of Anaplastic oligoastrocytoma WHO gr III intermediate differentiation WHO gr II-III

Pineoblastoma WHO gr IV Ependymal tumours Papillary tumour of the pineal region WHO gr II-III Subependymoma WHO gr I Myxopapillary WHO gr I Ependymoma WHO gr II Anaplastic ependymoma WHO gr III

WHO classification of CNS tumours 2/2

Embryonal tumours Tumours of the sellar region WHO gr IV WHO gr I CNS PNET WHO gr IV Granular cell tumour of the Atypical teratoid/rhabdoid tumour WHO gr IV Neurohypophysis WHO gr I WHO gr I Tumours of the cranial and paraspinal Spindle cell oncocytoma of the nerves Adenohypophysis WHO gr I

Schwannoma WHO gr I WHO gr I Tumours of the haematopoietic system Perineurioma WHO gr I-III Malignant lymphoma Malignant peripheral nerve sheath Histiocytic tumours tumour (MPNST) WHO gr II-IV Germ cell tumours Meningeal tumours WHO gr I Familial tumour syndromes Atypical meningioma WHO gr II Anaplastic meningioma WHO gr III Metastatic tumours Haemangiopericytoma WHO gr II Anaplastic haemangiopericytoma WHO gr III Melanocytic lesions Haemangioblastoma WHO gr I

WHO grading Prognosis and

• Histological grading is a means of survival predicting biological behaviour and influences choice of therapies. • WHO grade, age, performance status, • Grade I lesions: generally low tumour location; radiology (eg contrast proliferative potential; possibility of enhancement), extent of surgical cure following surgical resection alone. resection; proliferation indices; genetic alterations • Grade II lesions: generally infiltrative, have low level proliferative activity but often recur; some progress • WHO Gr II: typically survive >5yrs to higher grade malignancy. • WHO Gr III: typically survive 2-3yrs • Grade III lesions: generally have • WHO Gr IV: GBM typically succumb histologic evidence of malignancy within a year. Others such as (atypia, mitoses); most receive medulloblastoma and germ cell adjuvant radiation and/or chemo. tumours are rapidly fatal if untreated, Grade IV lesions: are cytologically but radiation and chemotherapy result malignant, mitotically active, necrosis- in 5-yr survival 60% & 80% prone; ass w rapid disease evolution respectively. and fatal outcome. Eg GBM, most embryonal tumours and many sarcomas. Some tend to have widespread infiltration and propensity for craniospinal dissemination.

Preoperative differential diagnosis

1) Patient details: Age 2) Radiology: Site, intra or (adult or child), gender (eg extra axial, met breast CA), known supratentorial or tumours, previous infratentorial, pattern of therapy (eg irradiation), enhancement, solid or rapid onset, immuno- cystic, necrosis, compromised (eg tumour, haemorrhage, margins, abscess, CNS lymphoma, calcification. PML), genetic disorders 3) Surgeon’s (eg NF, TS, Turcot’s) observations

Common CNS tumours by location, age and imaging characteristics 1/4

Location Child / Young adult Older adult

Cerebral / Ganglioglioma (TL, cyst-MEN, E) Diffuse Gr II-III (NE, focal E) Supratentorial DNET (TL, intracortical nodules) GBM (E or rim E, “butterfly”) PNET (solid, E) Metastases (grey-white juncn, E or rim E) AT/RT (infant, E) Lymphoma (periventricular, E)

Cerebellar / PA (cyst-MEN) Metastases (multiple, E or rim E) 4th ventricle Medulloblastoma (vermis, E) (cyst-MEN) Ependymoma (4th v, E) (4th v, E) Choroid plexus papilloma (4thv, E) AT/RT (infant, E)

Brainstem “” (pons, +/-E) Gliomatosis cerebri (multifocal, +/-E) PA (dorsal, exophytic, cyst-MEN)

AT/RT, Atypical teratoid/rhabdoid tumour; DNET, Dysembyoplastic neuroepithelial tumour; E, Enhancing; GBM, Glioblastoma multiforme; MEN, Mural enhancing nodule; PA, ; PNET; Primitive neuroectodermal tumour; TL, Temporal lobe Common CNS tumours by location, age and imaging characteristics 2/4 Location Child / Young adult Older adult

Spinal cord Ependymoma (E, +/- syrinx) Ependymoma (E, +/- syrinx) (intramedullary) PA (cystic, E) Diffuse astrocytoma (ill defined, +/-E Drop metastases (cauda equina, E) MPE (filum terminale, E) MPE (filum terminale, E) Paraganglioma (filum terminale, E)

Spinal cord Clear cell meningioma (+/- dural tail, E) (nerve origin, dumbbell (intradural, Schwannoma (NF2, nerve origin, shape, E) extramedullary) dumbbell shape, E) Meningioma (+/- dural tail, E) Drop metastases (leptomeningeal, E)

Spinal cord Bone tumour spread (EWS/PNET, Herniated disc (T1-spin echo, NE) (extradural) usually E) Postoperative scar (E) Meningioma (+/- dural tail, E) Secondary lymphoma (E) Abscess (E) Metastases (E) Vascular malformations (dilated BV, Abscess (E) +/- E)

BV, blood vessels; E, Enhancing; EWS: Ewing’s sarcoma; MPE, Myxopaillary ependymoma; NE, non enhancing PNET; Primitive neuroectodermal tumour; Common CNS tumours by location, age and imaging characteristics 3/4

Location Child / Young adult Older adult Intrasellar Pituitary adenoma (solid, E) Pituitary adenoma (solid, E) Craniopharyngioma (cystic, E) Craniopharyngioma (cystic, E) Rathke’s cleft cyst (cystic, +/- E) Rathke’s cleft cyst (cystic, +/- E)

Suprasellar / Germinoma (solid, E) Colloid cyst (3rd v, +/- E) hypothalamic/ Craniopharyngioma (cystic, E) Craniopharyngioma (cystic, E) optic pathway/ PA (cyst-MEN) 3rd ventricle Pilomyxoid astrocytoma (infant, solid, E)

Pineal Germinoma (solid, E) Pineocytoma (solid, E) Pineocytoma (solid, E) Pineal cyst (cystic, NE) Pineoblastoma (solid, E) Pineal cyst (cystic, NE)

Thalamus PA (cyst-MEN) AA/GBM (E or rim E) AA/GBM (E or rim E) Lymphoma (E, +/- multifocal)

AA, Anaplastic astrocytoma; E, Enhancing; GBM, Glioblastoma; MEN, mural enhancing nodule; NE, non enhancing; PA, Pilocytic astrocytoma; Common CNS tumours by location, age and imaging characteristics 4/4 Location Child / Young adult Older adult

Cerebellopontine Vestibular schwannoma (NF2, E, Vestibular schwannoma (NF2, E, angle involves internal auditory meatus) involves internal auditory meatus) Choroid plexus tumour (E, Meningioma (+/- dural tail, E) component in 4th v)

Lateral ventricle (E) Central neurocytoma (E) SEGA (tuberous sclerosis, E) SEGA (tuberous sclerosis, E) Choroid plexus papilloma (E) Choroid plexus papilloma (E) (infant, Subependymoma (+/- E) E, large, invasive) Meningioma (+/- dural tail, E)

Nerve root / Neurofibroma (NF1, E) Schwannoma (dumbbell shape, E) paraspinal MPNST (NF1, E, necrotic) Meningioma (+/- dural tail, E) Secondary lymphoma (E) Neurofibroma (NF1, E) MPNST (E, necrotic)

E, Enhancing; MPNST, malignant peripheral nerve sheath tumour; NF1, type 1 SEGA, subependymal giant cell astrocytoma Anatomical distribution of commonest brain tumours in adults.

Anatomical distribution of commonest brain tumours in children.

Interpreting the MRI • 3 planes of section

Axial (this has all the T1, T2, etc thus go to that plane),

Coronal, Sagittal (latter 2 would usually only have T1 post contrast)

Axial Coronal Sagittal Interpreting the MRI

• 4 main sequences Thus if cortex is brighter (hyperintense) than white T1 pre, T1 post contrast matter = T2 (vice versa in T1 where (gadolinium – look for bright BV & choroid plexus CSF is also black) compared with pre contrast ), T2, T2-flair (CSF is suppressed) III. Contrast enhancement is assessed on T1 (not on T2; thus do • 3 simple principles not confuse T2 brightness for contrast enhancement) NB: Blood is bright on the I. On T2 = H2O (CSF, oedema) T1 pre contrast, thus need to compare T1 II. White matter is rich in lipid myelin, pre and post)

thus contains less water than grey matter, thus white matter is darker • For quick intraoperative (hypointense) than grey matter on look, pick T1 post (for T2 enhancement) and T2-flair (for extent of lesion including oedema) sequences on the axial planes.

T1 pre T1 post

Cortex is darker than white matter Contrast indicated by bright blood Vessels and choroid plexus T1 pre T1 post

Enhancing lesion (GBM) T2 T2 flair

Cortex brighter than white matter Fluid attenuated: ie brightness of CSF CSF is bright is attenuated and is now dark. T2 T2 flair

Cortex brighter than white matter With CSF suppressed, water such as CSF is bright Oedema can be assessed better (Anaplastic astrocytoma) NB: Oedema (& CSF) are dark on T1 Other T2 based MRI sequences

1. DWI: Diffusion – Weighted Imaging 2. T2-GRE (T2*): Gradient Echo • “Restricted diffusion” - • Useful for detecting (appears hypointense/dark) Bright on DWI Movement of water is o Blood products (eg cavernoma) “restricted” in o In acute infarct (6hr-7d), o Iron o Calcium o Abscess (eg helpful in a ring enhancing lesion with ddx GBM, met), o Epidermoid cyst, 3. SWI: Susceptibility-Weighted Imaging o Hypercellular tumours (PCNSL, • Useful for detecting (appears PNET, etc) hypointense/dark) o Blood products o Iron o Calcium o Small veins

Information to be gained on MRI

1. Anatomic location 4. Pattern of contrast enhancement 2. Interface of lesion • Smooth ring: Abscess (confirm with DWI) border with brain • Ragged ring: GBM, Met • Sharply circumscribed: eg Met, • C-shaped ring: Demyelinating PXA, PA, ganglioglioma, hemangioblastoma • Solid, uniform: Meningioma (look for dural tail), PCNSL (NB HIV can have necrosis), • Diffuse: 2 things - Diffuse gliomas & Schwannoma (ie no central necrosis, slow growing, lymphomas LG, except lymphoma)

NB: Half of diffuse gliomas invade cortex & • Cyst w nodule: PA, PXA, blurs gray/white on T2-flair (cf Ganglioglioma vasogenic edema is limited by • Dark ring*: Cavernoma, Abscess gray/white)

* T2, T2-flair, T2-GRE, T2-SWI 3. Presence of contrast

enhancement • Eg GBM (strong), JPA (uniform), etc

Patterns of contrast enhancement

 Meningioma: Solid uniform enhancement; dural tail

Abscess: Uniformly thick  GBM: Ragged ring & smooth contoured ring enhancement. (NB: Fluid diffusion restricted On DWI) Pilocytic astrocytoma:  Cystic with enhancing nodule HISTOPATHOLOGIC ASSESSMENT

Combination of • Histopathology - patterns

• Immunohistochemistry - Glial markers: GFAP, S100 - Neuronal markers: Synaptophysin, chromogranin, NeuN (mature neuronal diff), NFP (axons) - Epithelial markers: CK - Proliferation markers: Ki67 - Prognostic: IDH1

• Molecular studies - FISH: 1p19q deletion (oligo), N-myc or c-myc (in large cell/anaplastic medulloblastoma)

Normal brain

Astrocytes (arrowhead) (arrow) (Pyramidal) neurones

Smear cytologic Preparation  Some neoplastic patterns

Diffuse hypercellular parenchymal infiltrate Discrete circumscribed mass (glioma) (eg metastatic adenocarcinoma) Some neoplastic patterns

“Fried egg” or Clear cells: Eg Oligodendro- Biphasic (loose and compact): Eg PA, PXA, glioma, small cell GBM, clear cell ependymoma, Ganglioglioma, Schwannoma central neurocytoma Some neoplastic patterns

Pseudo/Palisading cells: GBM Rosenthal fibres / Eosinophilic granular (pseudopalisading necrosis), Bodies: PA, ganglioglioma, PXA, piloid gliosis Schwannoma (Verocay bodies) adjacent slow growing neoplasms Some neoplastic patterns

“Small blue cells” (Primitive): Medulloblastoma, Rosette forming: Eg Ependymoma (true CNS PNET, AT/RT, GBM, lymphoma, rosette), Medulloblastoma (Homer Wright), melanoma CNS PNET

• Diffusely infiltrating astrocytomas: Grading is based on areas showing highest Low gr diffuse astrocytoma, anaplastic anaplasia. astrocytoma, GBM Diffuse Grade II: Cytologic atypia alone • Circumscribed astrocytomas: Anaplastic Grade III: Anaplasia & mitoses Pilocytic astrocytoma, Pleomorphic Glioblastoma Grade IV: Vascular xanthoastrocytoma (PXA) endothelial proliferation and/or necrosis • Most frequent intracranial neoplasms (>60% of all 1o brain tumours) Definitions: • Diffuse astrocytomas share the • Atypia: variation in nuclear shape or following features: size with hyperchromasia 1) arise at any CNS site, preferentially • Mitoses: must be unequivocal (but no in cerebral hemispheres, number criteria). A single mitosis does 2) usu manifest clinically in adults, not confer gr III behaviour (may do Ki67 3) diffuse infiltration of adjacent brain immunostain: a proliferative marker) and structures irrespective of grade, • Microvascular (vascular endothelial) 4) tendency for progression to proliferation: Apparent multilayering of anaplasia (anaplastic or GBM) endothelium or glomeruloid vasculature • Recurrent lesions tend to be of a • Necrosis: May be of any type; higher grade than the previous perinecrotic palisading need not be resection. present.

Normal white matter: Oligodendroglial cells predominate: small, round, dark. : larger oval nuclei. Grade II Astrocytoma: Increased cellularity, moderate pleomorphism (less in oligo), “naked” oval (round in oligo) nuclei devoid of cytoplasm, moderately coarse chromatin (fine in oligo), indistinct nucleoli (often present in oligo), fibrillary processes. Grade III Anaplastic astrocytoma: Increased pleomorphism, mitoses. Grade IV GBM: Vascular endothelial proliferation Grade IV GBM: Palisaded necrosis Grade II Oligoastrocytoma: Oligodendroglial component on left, astrocytic component on right.

Timing and frequency of genetic alterations in the evolution of glioblastoma Practical molecular classification of diffuse gliomas • There are currently only 2 clinically relevant (diagnostic, prognostic and predictive) diffuse glioma molecular markers - 1p/19q codeletion - Isocitrate Dehydrogenase (IDH) mutation 1p19q co-deletion

• 5-10% of all primary brain tumours are • Presence of 1p19q co-deletion: a.Diagnostic role: To refine • FISH studies classification of gliomas and • 1p19q found in support an oligodendroglioma component. - LG oligodendrogliomas: Nearly 85% b.Prognostic (longer survival) in - Anaplastic oligodendrogliomas: 65% anaplastic and probably also for - GBM with oligo component: 5-15% LG gliomas. This is • Probably an early event in inconsistent for GBM with oligo. tumorigenesis. NB: Prognostic significance of 1p del without 19q del and vice versa is not • High inter-observer variation in definitely understood. diagnosing an oligodendroglioma c.Predictive: Chemosensitive component.

• Thus co-deletion is a favourable genetic signature, correlates with oligodendroglioma morphology (it is the molecular definition of oligo) and impacts treatment regimen. IDH1/2 mutation • Originally discovered in 2008 • Presence of IDH1/2 mutation: • IDH1 mutation is most common a.Diagnostic role: Nil. (95%). IDH1(R132H) NB: Not in pilocytic astrocytoma Gr I

immunohistochemistry available b.Prognostic: Better survival • IDH1/2 mutation found in than gliomas with wild-type - LG (WHO gr II) gliomas: 70-80% IDH. - Anaplastic (gr III) glioma: 65-70% - Including all 1p19q codeleted oligos c.Predictive: Not currently - Secondary GBM (gr IV): >80% predictive for outcome to a BUT only specific therapy - Primary GBM (gr IV): <10% • Probably an early tumour event (like • Thus mutation is a favourable 1p19q co-del and p53). genetic signature which is used to stratify grade II-III • IDH1Often occurs with p53 mutation in astrocytoma gliomas • P53 and 1p19q del are generally mutually exclusive

MGMT promoter methylation

• A methylated (thus silenced) MGMT • MGMT promoter methylation: promoter, encoding a DNA-repair a.Diagnostic role: Nil. enzyme, is present in many cancers including b.Prognostic: - LG (WHO gr II) gliomas: up to 93% - Anaplastic (gr III) glioma: 50-80% c.Predictive: Partially predictive - Secondary GBM (gr IV): 70% of enhanced response to DNA - Primary GBM (gr IV): 40% alkylating chemotherapeutics (temozolomide) and benefit • Not routinely tested. Antibodies are from radiotherapy. However available for detection of MGMT standard of care of GBM is protein, but interpretation is radiotherapy + temozolomide challenging. regardless of MGMT status.

EGFR mutation

• Typically in GBM (45%, especially • MGMT promoter methylation: small cell GBM 70%) and anaplastic a.Diagnostic role: In GBM and astrocytoma (10%), rather than AA, but not oligo (eg anaplastic oligo). oligodendroglioma. b.Prognostic: Inconclusive

c.Predictive: EGFR tyrosine kinase inhibitors (TKI) in clinical trial settings.

CONCLUSION

• CNS tumour • Gliomas  GBM, astrocytomas and classification oligodendrogliomas are the  Cell of origin commonest primary brain

 Tumour grading neoplasms

 Molecular

• Pre/Intraoperative • Molecular differential classification of diffuse gliomas (gr II-III) diagnosis with 1p19q codeletion and IDH1  Age (adult vs paediatric), mutation status have become

 Tumour site routine practice

 Radiologic characteristics (circumscribed vs diffuse, enhancing vs non-enhancing, pattern of enhancement)