Neuropathology tumours

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The article covers tumours in neuropathology. Tumours are a large part of neuropathology. Cytopathology of CNS tumours is dealt with in the article CNS cytopathology.

There are separate articles for peripheral nerve sheath tumours and pituitary/peri-pituitary lesions.

Brain tumours - overview

Adult

Four most common types of brain tumours:[1]

  1. Metastatic brain tumours (barely edges out primary tumours)
  2. Glioblastoma (previously known as glioblastoma multiforme).
  3. Anaplastic astrocytoma.
  4. Meningioma.

Children

  1. Astrocytoma.
  2. Medulloblastoma.
  3. Ependymoma.

Location (most common)

Certain tumours like to hang-out at certain places:[2]

Filum terminale

  • Filum terminale = bottom end of the spinal cord - has a limited differential.

DDx:[3]

Cerebellopontine angle

DDx:[4]

Cystic tumours

DDx:[5]

Primary versus secondary

  • AKA (primary) brain tumour versus metastatic cancer.

Primary

Glial tumours:

  • Cytoplasmic processes - key feature.
    • Best seen at highest magnification - usu. ~1 micrometer.
    • Processes may branch.
  • Ill-defined border/blend with the surrounding brain.

Lymphoma:

  • Large (lymphoid) cells, ergo usu. not a difficult diagnosis.
    • ~2x size of resting lymphocyte, nucleoli.
  • Lesion predominantly perivascular.

Secondary

Carcinomas:

  • Well-demarcated border between brain and lesion - key feature.
  • No cytoplasmic processes.
  • Usu. have nuclear atypia of malignancy.
    • Nuclei often ~3-4x the size of a RBC.
  • +/-Glandular arrangement.
  • +/-Nucleoli.

Common neuropathology tumours in a table

Type Key feature(s) Imaging History Notes IHC Images
Normal tissue cells regularly spaced, no nuc. atypia small lesion? / deep lesion? variable missed lesion? nil very high mag., high mag.
Reactive astrocytes astrocytes with well-demarcated eosinophilic cytoplasm, regular spacing, no nuc. atypia small lesion? / deep lesion? variable missed lesion / close to a lesion; non-specific pathologic process - need more tissue nil high mag.
Astrocytoma (grade II or worse) glial processes (esp. on smear), nuclear atypia (size var. ~3x, irreg. nuc. membrane, hyperchromasia), no Rosenthal fibres in the core of the lesion † often enhancing (suggests high grade), usu. supratentorial, usu. white matter usu. old, occ. young very common, esp. glioblastoma IDH-1+/-, GFAP+ high mag., very high mag.
Metastasis sharp interface with brain, often glandular, +/-nucleoli, no glial processes often cerebellular, well-circumscribed usu. old often suspected to have metastatic disease TTF-1, CK7, CK20, BRST-2 very low mag., high mag.
Meningioma whorls, psammomatous calcs, nuclear inclusions extra-axial + intradural old or young may be diagnosed on smear, DDx: choroid plexus, schwannoma EMA, PR, Ki-67 intermed. mag.
Schwannoma cellular areas (Antoni A), paucicelluar areas (Antoni B), palisading of nuclei (Verocay bodies) extra-axial + intradural old or young need frozen section to Dx S100 intermed. mag.,

very high mag.

† Rosenthal fibres at the periphery of a lesion are a non-specific finding seen in chronic processes.

Metastatic brain tumours

General

Microscopic

Appearance varies by subtype.

Features of metastatic carcinoma:

  • Tubule formation/glands.
  • Usually well-circumscribed/sharply demarcated from surrounding tissue.
  • Usually nuclear atypia including:
    • Nuclear hyperchromasia.
    • Variation of nuclear size.
    • Variation of nuclear shape.
  • Mitoses - common.

DDx:

Images:

IHC

  • Carcinoma: pankeratin +ve.
    • Lung adenocarcinoma and SCLC: TTF-1 +ve, CK7 +ve, CK20 -ve.
    • Breast carcinoma: CK7 +ve, ER +ve, PR +ve, BRST2 +ve/-ve.
    • Colorectal carcinoma: CK7 -ve, CK20 +ve, CDX2 +ve, TTF-1 -ve.

Infiltrative astrocytomas

Overview

  • Low-grade (diffuse) astrocytomas (Grade II).
  • Anaplastic astrocytomas (Grade III).
  • Glioblastoma (Grade IV).

Notes:

Microscopic

Features:[7][8]

  • Glial processes - key feature.
    • Thin stringy cytoplasmic processes - best seen at high power in less cellular areas.
  • No Rosenthal fibres within the tumour itself.

Images:

Notes:

  • Glial vs. non-glial tumours:
    • Glial: "blends into brain"/gradual transition to non-tumour brain.
    • Non-glial: no glial processes.
  • Rosenthal fibres within the tumour... make it into a pilocytic astrocytoma.
    • Rosenthal fibres may be seen around a (very) slow growing tumour and represent a reactive process.
  • Inflammatory cells and macrophages should prompt consideration of an alternate diagnosis (e.g. cerebral infarct, multiple sclerosis) - esp. if this is a primary lesion.[9]

Grading

Nuclear pleomorphism present:

  • At least grade II (diffuse astrocytoma).

Mitotic figures present:

  • At least grade III (anaplastic astrocytoma).

Microvascular proliferation or necrosis with pseudopalisading tumour cells:

  • Grade IV (glioblastoma AKA glioblastoma multiforme).

Notes:

  • Pseudopalisading tumour cells = high tumour cell density adjacent to regions of necrosis; palisade = a fence of pales forming a defense barrier or fortification.

Images:

Table of common gliomas - grading

Histomorphologic comparison of common gliomas:

Entity Rosenthal
fibres / EGBs
Nuclear atypia Mitoses Necrosis or MVP Infiltrative Image
Pilocytic astrocytoma yes usu. no usu. no usu. no no [1]
Low-grade astrocytoma no yes no no yes image?
Anaplastic astrocytoma no yes yes no yes [2]
Glioblastoma no yes yes yes yes [3]

Notes:

  • MVP = microvascular proliferation.
  • EGBs = eosinophilic granular bodies.

IHC

  • GFAP - should stain cytoplasm of tumour cells and the perikaryon (nuclear membrane).
  • Ki-67 - usu. high >20% of cells.
  • p53 - often +ve.
  • IDH1 (isocitrate dehydrogenase 1).

Notes:

  • IDH1 and IDH2 mutations - better survival.[11]

Pilocytic astrocytoma

General

  • Low-grade astrocytoma.
  • Classically in the cerebellum in children; most common glioma in children.[12]
  • The optic glioma associated with neurofibromatosis 1.

Gross

Features:[12]

  • Usually well-circumscribed.
  • Cystic or solid.
  • Do not smear. (Ref. ?)

Microscopic

Features:[13]

  • Classically biphasic (though either may be absent):
    1. Fibrillar.
    2. Microcystic/loose.
  • Hair-like fibres ~ 1 micrometer; pilo- = hair.[14]
    • Best seen on smear or with GFAP IHC.
  • Rosenthal fibres - key feature.
    • May be rare. Not pathognomonic (see below).
  • Eosinophilic granular bodies.
  • Low cellularity - when compared to medulloblastoma and ependymoma.

Notes:

  • +/-Microvascular proliferation.
  • +/-Focal necrosis.
    • Necrosis with pseudopalisading more likely glioblastoma.
  • +/-Mitoses - not significant in the context of the Dx.

DDx (of Rosenthal fibers):[15]

  • Chronic reactive gliosis.
  • Subependymoma.
  • Ganglioma.
  • Alexander's disease (rare leukodystrophy).

DDx of pilocystic astrocytoma (brief):

  • Piloid gliosis.
  • Oligodendroglioma.
  • Glioblastoma (uncommon - but important).

Images:

IHC/special stains

Features:[17]

  • GFAP +ve (fibres).
  • PAS-D: eosinophilic granular bodies +ve.
  • CD68: may have a significant macrophage component.
  • KI-67: may be "high" (~20% ???).

Grading

  • WHO Grade I by definition.

Pleomorphic xanthoastrocytoma

  • Abbreviated PXA.

General

Features:

  • Classically in the temporal lobe in children and young adults.
  • Associated with seizures.

Microscopic

Features:[18]

  • Marked nuclear atypia.
  • Inflammation (chronic).

Notes:

  • No mitoses.
  • No necrosis.

Images:

IHC

  • GFAP +ve.
  • CD68 +ve.

Dysembryoplastic neuroepithelial tumour

  • Abbreviated DNT.

General

  • Common tumour cause of drug resistant epilepsy.[19]
  • Paediatric population.

Gross/radiology

  • Temporal lobe.
  • Variable architecture:[20] cystic, solitary nodular, multinodular.

Microscopic

Features:[20]

  • Cells similar to oligodendrocytes:
    • Large central nuclei with indentations.
    • Multiple small nucleoli (common).
    • Clear cytoplasm.

DDx:

Images:

Subependymal giant cell astrocytoma

  • Abbreviated SEGA.

General

Gross/radiology

  • Well-demarcated.

Microscopic

Features:[22][23]

Images:

IHC

Features:[23]

  • GFAP +ve. (???)
  • Vimentin +ve. (???)
  • S100 +ve. (???)

Pilomyxoid astrocytoma

General

Features:[25]

  • A variant of pilocytic astrocytoma.
    • Some have suggested it is a unique entity.[26]
  • Childhood or adolescence.

Gross

Features:[25]

  • Classically - hypothalamic location/suprasellar location; may involve the sella turcica.[27]
  • Solid.
  • Well-circumscribed.

Microscopic

Features:[25]

  • Consists of small round/ovoid bland cells in a myxoid stroma.
  • Hair-like fibres ~ 1 micrometer.
    • Often difficult to appreciate on standard (H&E) histologic sections.
  • Usually angiocentric (surround blood vessel) - key feature.

Notes:[25]

  • Rosenthal fibres are absent - key negative.
  • Monophasic (unlike classical pilocytic astrocytomas) - key negative.
  • May rarely have eosinophilic granular bodies.

Grading

  • WHO Grade II by definition.[25]

Atypical teratoid/rhabdoid tumour

See also: Extrarenal malignant rhabdoid tumour.
  • Commonly abbreviated AT/RT.
  • May be written atypical teratoid rhabdoid tumour, i.e. without the forward slash, or atypical teratoid-rhabdoid tumour (AT-RT).

General

  • Usually supratentorial, occasionally in posterior fossa, case reports of spinal cord.

Microscopic

Features:

  • Cellular.
  • Small round cells usu. with a prominent nucleolus.
  • Rhabdoid cells.
    • Cells with eosinophilic granular cytoplasm + eccentric nucleus.
  • Mitoses.
  • +/-Necrosis (common).

DDx:

Images:

IHC

  • BAF-47 -ve (AKA INI1, AKA SMARCB1 - the HGNC symbol[28]) - virtually diagnostic.
    • Endothelial cells +ve control.
  • S-100 +ve.
    • Few other brain tumours express it.
  • Vimentin +ve (perinuclear condensation).

Others:

  • GFAP +ve (focal - in tumour cells).
  • EMA +ve (patchy cytoplasmic).
  • Smooth muscle actin +ve.

Oligodendroglioma

General

  • Do not arise from oligodendrocytes.
    • Arise from glial precursor cells.

Usual location:

  • Fourth ventricle.
  • Intramedullary spinal cord.

Prognosis by flavours (average survival):[29]

  • WHO grade II: 10-15 years.
  • WHO grade III: 3-5 years.

Microscopic

Features:

  • Highly cellular lesion composed of:
    • Cells resembling fried eggs (oligodendrocytes) with:
      • Round nucleus - key feature.
      • Distinct cell borders.
      • Moderate-to-marked nuclear atypia.
      • Clear cytoplasm - useful feature (if present).
        • Some oligodendrogliomas have eosinophilic cytoplasm with focal perinuclear clearing.
    • Acutely branched capillary sized vessels - "chicken-wire" like appearance.
      • Abundant, delicate appearing; may vaguely resemble a paraganglioma at low power.
  • Calcifications - important feature.[30]

Note:

  • Tumour cells may be plasmacytoid, i.e. have a plasma cell-like appearance.[31]

DDx:

  • Neurocytoma also have perinuclear clearing and well-defined cellular borders.
    • Pineocytomatous/neurocytic rosettes = (irregular) rosette with a large meshwork of fibers (neuropil) at the centre.

Notes:

Images:

Histologic grading

Come in two flavours:

  1. WHO grade II.
    • This is most oligodendrogliomas.
  2. WHO grade III.
    • Features for calling high grade:[29]
      • Endothelial hypertrophy.
        • Plump/large endothelial cells.
      • Necrosis.
      • High mitotic rate (6 mitoses/10 HPF for whatever "HPF" means, see HPFitis).

IHC

Features:

  • MAP-2 +ve.[32]
  • GFAP -ve.
    • Some subtypes +ve - should not be used to distinguish.[33]
  • EMA +ve.
  • IDH-1 -ve. (???).
  • p53 -ve.
    • Useful for differentiating astrocytoma vs. oligodendroglioma.
  • Ki-67.

Molecular pathology

Losses of 1p and 19q both helps with diagnosis and is prognostic:[34]

  • Greater chemosensitivity
  • Better prognosis.

Oligoastrocytoma

General

  • Mixed tumour.

Microscopic

Features:

  • Astrocytoma-like and oligodendroglioma-like:
    1. Oligodendroglioma-like cells = round nucleus, peri-nuclear clearing.
    2. Astrocytoma-like cells = non-ovoid/elongated nucleus.

DDx:

  • Anaplastic astrocytoma.
  • Oligodendroglioma. (???)

IHC

  • Oligodendroglioma-like cells: MAP-2 +ve (cytoplasm).
  • Astrocytoma-like cells: GFAP +ve (cytoplasm, nuclear membrane).

Others:

  • Ki-67 ~10%. (???)
  • p53 - focally +ve. (???)
  • IDH-1 -ve. (???)

Meningioma

General

  • Very common.
  • May be part of a syndrome.

Microscopic

Features (memory device WCN):

  • Whorled appearance - key feature.
  • Calcification, psammomatous.
  • Nuclear pseudoinclusions - focal nuclear clearing with a sharp interface to unremarkable chromatin.

Grading: see meningioma.

Peripheral nerve sheath tumours

A classification:[35]

Schwannoma

General

  • Tumour of tissue surrounding a nerve.
    • Axons adjacent to the tumour are normal... but may be compressed.

Microscopic

Features:[35]

  • Antoni A:
    • Cellular.
    • 'Fibrillary, polar, elongated'.
  • Antoni B:
    • Pauci-cellular.
    • Loose microcystic tissue.
  • Verocay bodies - paucinuclear area surrounded by palisaded nuclei.
  • In the GI tract: classically have a peripheral lymphoid cuff.[36]

Images:

Notes:

  • Several subtypes exist.

Neurofibroma

General

Microscopic

Features:

Image:

Ganglioneuroma

General

Gross

  • Solid.
  • White.
  • Firm.
  • Well-circumscribed.
  • May be nodular.

Images:

Microscopic

Features:

  • Ganglion cells - key feature.
    • Large cells with large nucleus.
      • Prominent nucleolus.
  • Disordered fibrinous-like material.
  • Eosinophilic granular bodies.[38]

Images:

See: adrenal ganglioneuroma, colonic ganglioneuroma.

Ependymoma

General

  • Called the forgotten glial tumour.

Epidemiology:[39]

  • Usual site:
    • Adults: usu. spinal cord.
    • Children: usu. posterior fossa.
  • May be assoc. with neurofibromatosis 2.

Comes in two main flavours:

  1. Ependymoma (not otherwise specified).
  2. Myxopapillary ependymoma.
    • Classically at filum terminale.

Other flavours:[40]

  • Papillary ependymoma.
  • Clear cell ependymoma.

Microscopic

Classic ependymoma

Features:

  • Cells have a "tadpole-like" morphology.
    • May also be described as ice cream cone-shaped.[41]
  • Rosettes = circular nuclear free zones/cells arranged in a pseudoglandular fashion; comes in two flavours in ependymoma:
    • Perivascular pseudorosettes = (tumour) cells arranged around a blood vessel; nuclei of cells distant from the blood vessel, i.e. rim of cytoplasm (from tumour cells) surround blood vessel (nucleus-free zone); more common than ependymal rosette... but less specific.
    • Ependymal rosette (AKA true ependymal rosette) = rosette has an empty space at the centre - key feature.
  • Nuclear features monotonous, i.e. "boring".[42]
    • There is little variation in size, shape and staining.

DDx (classic ependymoma):

Images:

Myxopapillary ependymoma

Features:

  • Perivascular pseudorosettes:
    • Myxoid material surround blood vessels.
      • Myxoid material surrounded by tumour cells.

Images:

Grading

Easy:

  • Subependymoma = WHO grade I.
  • Myxopapillary ependymoma = WHO grade I.

Not-so-easy:

  • Classic ependymoma = WHO grade II.
  • Anaplastic ependymoma = WHO grade III.

Grade II vs. Grade III:

  • Cellular density.
  • Mitoses.
  • Necrosis.
  • Microvascular proliferation.

Notes:

  • Many tumours fall between grade II and grade III. These are called "indeterminate" by many.

IHC

  • Reticulin.
  • GFAP.
  • MIB-1.

Subependymoma

General

  • Good prognosis - WHO Grade I.

Gross/radiology

  • Classic location: fourth ventricle.[43]
  • Well demarcated margin.
  • Usu. completely within the ventricle; does not extend into brain (like ependymomas).

Microscopic

Features:[44]

  • Microcysts with bluish material - give a spongy appearance at low magnification.
  • Nuclei cluster.
    • Described as "bundles of flowers".

Negatives.

  • No nuclear pleomorphism, no prominent nucleoli, no mitoses.

Images:

Choroid plexus papilloma

General

  • Benign - WHO grade I.[45]
  • Usu. laternal ventricle in kids.[46]

Microscopic

Features:

  • Simple epithelium.
  • Papillae.
  • Psammoma bodies.

Images:

Choroid plexus carcinoma

General

  • Usually pediatric population.
  • Malignant counterpart of choroid plexus papilloma.[47]
  • Poor prognosis - WHO grade III.[45]
  • Classically posterior fossa.
  • Intraventricular mass.

Microscopic

Features:[47]

DDx:

Images:

IHC

Features:[45]

  • Cytokeratins +ve.
  • EMA usu. -ve.
  • GFAP -ve (~20% +ve).
  • Ki-67 high.
    • Useful to diff. from benign counterpart.
  • INI1 +ve.

Chordoma

General

  • Location: usually sacrum or clivus.
  • It is a bone tumour.

Microscopic

Features:[48]

  • Architecture: islands of cells surrounded by fibrous tissue.
    • Also described as "lobulated" architecture; may not be apparent.
  • Myxoid background - grey extracellular material, variable amount present.
  • Mixed cell population:
    1. Abundant eosinophilic cytoplasm.
    2. Physaliphorous cells or bubble cells - key feature.
      • Have a very large clear bubble with a sharp border; bubble does not compress nucleus - nucleus may be in bubble.

DDx:

Images:

IHC

Features:[49]

  • S100 +ve.
  • AE1/AE3 +ve.
  • Brachyury +ve -- key stain.
    • Protein important for axial development, affects notochord development.[50]
    • Brachyury literally means short tail.[51]

Hemangioblastoma

General

Microscopic

Features:[53]

  • Vascular.
  • Polygonal stromal cells with:
    • Hyperchromatic nuclei.
    • Vacuolar cytoplasm.

DDx:

Images:

IHC

Features:[54]

  • Alpha-inhibin +ve (cytoplasm).
  • EMA -ve.
    • RCC typically +ve.
  • NSE +ve (nucleus + cytoplasm).
    • RCC typically -ve.

Medulloblastoma

General

Gross

Microscopic

Features:[55]

Images:

DDx:

Subtypes

  • Classic medulloblastoma (~85% of all medulloblastomas).
  • Variants of medulloblastoma (~15% of all medulloblastomas together):
    1. Anaplastic variant.
    2. Large cell variant.
    3. Desmoplastic/nodular medulloblastoma (DNMB).
    4. Medulloblastoma with extensive nodularity (MBEN).

Notes:

  • Prognosis:[57][58] DNMB & MBEN > classic > anaplastic variant, large cell variant.
Anaplastic variant

Features:

  • Larger cells.
  • Severe anaplasia.
  • Polygonal cells.

Primitive neuroectodermal tumour

  • AKA primitive neuroepithelial tumour. (???)

General

  • Abbreviated PNET.
  • Should not be confused with peripheral primitive neuroectodermal tumour (abbreviated pPNET[59]), AKA Ewing sarcoma.

Microscopic

Features:

DDx:

Images:

Embryonal tumour with abundant neuropil and true rosettes

  • Abbreviated ETANTR.

General

  • Super rare.
  • Reported only in children <4 years old.[61]

Microscopic

Features:[62]

DDx:

Images:

CNS lymphoma

Classification:

  • Primary CNS lymphoma.
  • Non-primary CNS lymphoma - see lymphoma article.

General - primary CNS

  • Classically periventicular distribution.
  • Usually large B cell; can be considered a type of diffuse large B cell lymphoma (DLBCL).
    • Prognosis of CNS (DLBCL) lymphomas worse than nodal (non-CNS) DLBCL.[63]

Microscopic

Features:

  • Large cell lymphoma.
    • Size = 2x diameter normal lymphocyte.
    • Nucleolus - common.
  • Perivascular clustering.

Images:

IHC

Can be subclassified in GCB (germinal centre B-cell-like) and non-GCB by CD10, Bcl-6, MUM1/IRF-4, and Bcl-2.[63]

Common pattern:

  • CD20 +ve - key stain.
  • CD3 -ve.
  • Ki-67 ~40%.
  • Bcl-6 +ve.
  • Bcl-1 -ve.

Neurocytoma

General

  • Rare.

Microscopic

Features:[64]

  • Pineocytomatous/neurocytic rosette = irregular rosette with a large meshwork of fibers (neuropil) at the centre.[61]
    • Similar to Homer-Wright rosette.
  • Perinuclear clearing.
  • Well-defined cell borders.

DDx:

Images:

IHC

  • Synaptophysin +ve.
    • Most glial tumour -ve.[65]

Central neurocytoma

  • Abbreviated CNC.

General

  • Rare - less than 1% of brain tumours.[66]
  • Benign.
  • First described in 1982.[66]

Gross/radiology

  • Intraventricular.[67]
    • Characteristically attached to the septum pellucidum.[68]

Microscopic

Features:[69]

  • Perivascular pseudorosette = circular/flower-like arrangement of cells with blood vessel at the centre.[61]
  • Islands of neuropil.
  • Polygonal cells with a perinuclear halo.

DDx:

DDx of perivascular pseudorosette:

Images:

IHC

  • MIB-1 - high may predict re-occurance.[70]

Ganglioglioma

Not to be confused with ganglioneuroma.

General

  • Rare.
  • Usu. temporal lobe.
  • Recognized as a cause of epilepsy.[71]

Microscopic

Features:

  • Atypical neurons.
  • Atypical glia.

Images:

Lhermitte-Duclos disease

  • Abbreviated LDD.
  • AKA dysplastic cerebellar gangliocytoma.[72]
  • AKA dysplastic gangliocytoma of the cerebellum.

General

Microscopic

Features:[74]

  • The outer (molecular) layer has increased cellularity.
  • Purkinje cells absent.[72]
  • Large (polygonal) cells with round nuclei and prominent nucleoli in the inner (granular) layer - key feature.
  • +/-Microcalcifications.

Images:

Ganglioneuroblastoma

General

  • Uncommon.
  • Part of the neuroblastic tumours group which includes:[75]

Microscopic

Features:

  • Ganglion-like cells with a prominent nucleolus.
  • Small undifferentiated cells with scant cytoplasm.

Images:

IHC

  • NSE +ve -- small cells.

Lesions of the sella turcica

Lesions of the sella turcica, the pituitary gland environs, is a topic for it self. The differential diagnosis for lesions in this area includes:

See also

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