© illustration, cellular pathology, oxford radcliffe … · enhancing frontal lesion ......

Neuropathology

Dr Olaf Ansorge

Oxford

Oxford Pathology Course 2010For FRCPath

© Illustration, Cellular Pathology, Oxford Radcliffe NHS Trust

Neuropathology Ð 40 cases


Neuropathology Ð Neoplasia: Case 1

Clinical data:M, 47, single seizure, no neurological deficit, non-

enhancing frontal lesion

Slides: Biopsy HE, GFAP, MIB-1, p53

Diagnosis:Diffuse astrocytoma , WHO grade II

Comment:Mild hypercellularity and nuclear atypia only. No

mitoses or vascular proliferation. GFAP expression,low MIB-1, strong p53 overexpression


GFAP



MIB-1



p53




Clinical data:M, 56, one week of headaches, one seizure, ring-

enhancing left-parietal lesion

Slides: Biopsy HE, GFAP, MIB-1

Diagnosis:Glioblastoma multiforme, WHO grade IV

Comment: Very hypercellular and pleomorphic. Many mitoses and

vascular proliferation. Necrosis with pseudopalisading,high MIB-1


GFAP



MIB-1




Clinical data:M, 9, increasing lethargy over the past year, cystic

posterior fossa tumour

Slides:CSF MGG, smear methylene blue, biopsy HE

Diagnosis: Pilocytic astrocytoma , WHO grade I

Comment:Compact and reticular areas, Rosenthal fibres,

vascular proliferation (not indicative of malignancy inthis entity!), no mitoses


Arrow: Rosenthal fibre on smear



Vascular proliferation



Many Rosenthal fibres




Clinical data: M, 31, seizures x1 per week, frequency recently increasing. MRI Ð

large diffuse cortical and white matter lesion, non-enhancing.

Slides: Biopsy HE, GFAP

Diagnosis: Oligodendroglioma, WHO grade II

Comment: This is a very classical example. Note relative monomorphism and

roundness of cells and nuclei, ÔhalosÕ, and delicate reticular capillarynetwork. Oligos usually show some form of GFAP expression but thepattern is generally distinct from that of astrocytomas


GFAP




Clinical data: M, 35, progressive leg numbness and incontinence.

Slides: Biopsy HE x1, SYN, CD34

Diagnosis: Myxopapillary ependymoma, WHO grade I

Comment: This type of ependymoma occurs virtually always at the conus / filum

terminale of the spinal cord. Note the myxoid matrix and elongatedspindle cells with some perivascular rosetting. Vessels are oftenhyalinised. It is the only grade I ependymoma and usually well-encapsulated rather than infiltrating.



PAS-Alcian blue



Clinical data: F, 15, short history of headache, left frontal tumour close to lateral

horn.

Slides: Biopsy HE x2, GFAP, EMA

Diagnosis: Anaplastic ependymoma, WHO grade III

Comment: This example contains all features of neoplastic aberrant ependymal

differentiation: perivascular pseudorosettes, true ependymal rosetteswith a lumen, and ependymal canals/free surfaces. GFAP isaccentuated around the perivascular rosettes, ependymal lumina andsurfaces are EMA positive. Widespread necrosis, mitoses andvascular proliferation make it grade III


GFAP



EMA




Clinical data: M, 1, rapidly progressive lethargy, vomiting. Large frontal tumour on

imaging.

Slides: HE, SYN, CD34

Diagnosis: Ependymoblastoma, WHO grade IV

Comment: The ependymoblastoma is a rare tumour and an example of the

supratentorial PNET family. Characteristic are the ÔtrueÕependymoblastic rosettes without a central vessel and multilayeredrosetting cells with mitoses. There is often synaptophysinexpression, characteristic of PNETs, rather than GFAP, which isseen in classical grade I (myxopapillary) and grade II and IIIependymomas.



Clinical data: M, 1, lethargy, bouts of projectile vomiting. Large posterior fossa

tumour on imaging.

Slides: Smear methylene blue, biopsy HE, PM cerebellum HE

Diagnosis: Medulloblastoma, WHO grade IV

Comment: The medulloblastoma shares appearances of Ôsmall blue round cellÕ

tumours. It can be viewed as a PNET of the cerebellum. Significantnodularity (= increased differentiation) may confer a betterprognosis. Synaptophysin or GFAP may be expressed



Clinical data: F, 34, 6/12 headache/vomiting, worse over last week. Papilloedema.

Lateral ventricle tumour.

Slides: HE, GFAP, synaptophysin, NeuN (neuronal nuclei)

Diagnosis: Central neurocytoma, WHO grade II

Comment: Central neurocytomas virtually always arise within the lateral

ventricles close to the foramen of Monro. They are usuallymonomorphic and may be mistaken for oligodendrogliomas.Immunocytochemistry to confirm neuronal lineage is key.



GFAP



Synaptophysin NeuN



Clinical data: F, 13, 4 years of temporal lobe epilepsy, partially cystic tumour left

mesial temporal lobe.

Slides: HE, GFAP, chromogranin

Diagnosis: Ganglioglioma, WHO grade I

Comment: The temporal lobe is a typical site for ganglioglioma. Note the

atypical, occasionally multinucleate ganglion cells mixed withneoplastic astrocytes. The lymphocytic inflammation and calcificationis typical. Mitoses are usually absent. Some ganglioid cells co-express glial and neuronal markers. The prognosis is very good andprogression to high-grade lesions rare.



Chromogranin GFAP



Clinical data: 2 different cases. F, 58, occipital tumour (extrinsic). M, 27, convexity

enhancing tumour, well-defined.

Slides: Smear methylene blue, biopsies HE x2, EMA

Diagnosis: a. Meningioma (classical), b. meningioma (microcystic), both WHO

grade I

Comment: Plump spindle cells with whorls are classic. There are many variants

without clinical significance, but they can be diagnosticallychallenging. Most however contain a focus of the classical pattern,EMA can help


Case (a)



Case (b)



EMA, case (b)




Clinical data: M, 62, 9/12 slowly progressive weakness. Enhancing parietal lesion

with dural base.

Slides: HE, GFAP

Diagnosis: Atypical meningioma, WHO grade II

Comment: Criteria for atypia in meningiomas include: loss of architecture

(ÔsheetingÕ), macronucleoli, multifocal necrosis, brain invasion, and aÔhighÕ mitotic rate (>4/10HPF according to the WHO). Usually acombination of these factors is taken into account when making thisdiagnosis. Some rare meningioma variants are primarily grade II orhigher (e.g. clear cell, chordoid variants).



GFAP



Clinical data: F, 52, previous dx meningioma (8/12 ago); now very large recurrence

left parietal.

Slides: HE, CD34

Diagnosis: Solitary fibrous tumour of the meninges

Comment: SFTs sometimes have been mistaken for fibroblastic meningiomas.

However, the focally ÔgapingÕ vessels, alternating strands of collagen-rich and myxoid areas, plumper cytology, and, most significantly,diffuse CD34-positivity combined with EMA-negativity are obviouswhen this entity is considered. The main differential diagnosis ishaemangiopericytoma (see case 12).



CD34



Clinical data: M, 43, 4/12 headache latterly confusion. Papilloedema, large frontal

dural-based tumour.

Slides: HE, reticulin, CD34

Diagnosis: Haemangiopericytoma of the meninges

Comment: Haemangiopericytomas can be distinguished from SFTs by their

cytology and more ÔcrowdedÕ sheet-like architecture lacking thefibrous strands and myxoid/hypocellular areas of SFTs. ClassicalÔstag-hornÕ vessels are present and there is a dense pericellularreticulin network. CD34 expression is usually weak and patchy.



Reticulin CD34



Clinical data: M, 16, 4/12 headache/vomiting, worse over last week. Papilloedema,

cerebellar signs. Cystic post fossa lesion.

Slides: Smear methylene blue, biopsy HE

Diagnosis: Cerebellar haemangioblastoma, WHO grade I

Comment: Haemangioblastomas smear poorly; there is a mixture of dense

capillaries and plump vacuolated cells. Mast cells may be present.The HE shows the neoplastic ÔfoamyÕ cells much better. Thecapillaries are induced, not neoplastic. Haemangioblastoma mayindicate VHL syndrome.



Clinical data: M, 52, slowly progressive deafness left ear, recently unsteadiness,

cerebello-pontine angle tumour.

Slides: HE

Diagnosis: Schwannoma (WHO grade I)

Comment: Cranial nerve schwannomas do not show classical Verocay bodies

as commonly as peripheral nerve tumours. There may be significantdegenerative change manifesting as cellular pleomorphism, cysts,hyalinised vessels and haemosiderin deposition.



Clinical data: M, 18, occipital scalp lump, patient has NF1.

Slides: Biopsy HE, S100

Diagnosis: Malignant peripheral nerve sheath tumour (MPNST).

Comment: Note origin within a peripheral nerve and involvement of multiple

fascicles. A ÔschwannianÕ growth pattern is preserved in some areas;however appearances are mostly that of a highly malignant spindlecell tumour. S100 expression is surprisingly well preserved. If thereare no morphological features pointing to a specific lineagedifferentiation, an immunopanel for malignant soft tissue tumours isindicated.


S100




Clinical data: M, 52, nosebleed, headache; tumour in sphenoid/clivus. ENT biopsy

transnasally.

Slides: Biopsy HE, CK, synaptophysin, prolactin

Diagnosis: Prolactinoma, no aggressive features (WHO grade I)

Comment: Pituitary adenomas may sometimes present to ENT departments

where this diagnosis is not suspected. Pituitary hormoneimmunohistochemistry and synaptophysin are diagnostic. Some (notthis one) may be strongly CK positive. Review of the imaging in thiscase demonstrated a link to the sella, however ectopic tumours canoccur in the nasopharynx


Synaptophysin



Prolactin




Clinical data: M, 24, hemianopia, panhypopituitarism, cystic suprasellar tumour.

Slides: Cyst fluid cytospin MGG, Biopsy HE

Diagnosis: Adamantinomatous craniopharyngioma, WHO grade I

Comment: Foamy macrophages and negative imprints of Ôstate of UtahÕ

cholesterol crystals are typical in cytospins. The reticular pattern withpalisading basal epithelium and dead keratin is diagnostic. If youhave seen one, you have seen them all. The papillary variant isexceedingly rare.



Clinical data: M, 69, visual disturbances, headaches. Cystic tumour in the pituitary

fossa invading the skull base.

Slides: HE, PAS/AB, CK, S100.

Diagnosis: Chordoma.

Comment: Chordomas are related to remnants of the notochord and occur

mostly at the proximal and distal ends of the neuraxis. They are softtumours that are relentlessly invasive. PAS/AB highlights the intra-and extracellular mucins. Note the physalipherous cells (with giantvacuoles) and the combination of CK and S100 positivity(chondrosarcoma, the main DD, is CK negative).



PAS-OG CK



Clinical data: F, 10, diabetes insipidus since 12 months; slightly thickened

pituitary stalk

Slides: Biopsy HE, PLAP, c-kit.

Diagnosis: Suprasellar germinoma, WHO grade IV

Comment: A strong immune response to these tumours may lead to waxing

and waning symptoms and puzzling MRI findings. This is a classicexample with strong lymphocytic response with aberrant follicleformation. C-kit may be helpful because PLAP is often very weak


PLAP




Clinical data: M, 6, parents noted skull swelling, osteolytic lesion on CT.

Slides: HE, CD1a, S100.

Diagnosis: Eosinophilic granuloma (Langerhans cell histiocytocis).

Comment: The diagnosis is often not suspected clinically. This is a classical

example with well-formed CD1a-positive tumour cell aggregatesintermingled with eosinophils and a rim of lymphocytes at theperiphery. Extensive sampling may be necessary in cases withwidespread fibrosis.



CD1a



Clinical data: M, 51, visual disturbances, headaches, vomiting. Occipital contrast-

enhancing lesion. Otherwise well. ?glioblastoma.

Slides: Biopsy HE, CK7, CK20, TTF-1.

Diagnosis: Metastatic adenocarcinoma, c/w lung primary.

Comment: So-called Ômetastatic carcinomas of unknown originÕ are quite

common in surgical neuropathology. A limited immunopanel guidedby morphology can often pinpoint the likely primary site. This patientproved to have a large pulmonary mass (which was obvious on plainchest x-ray but missed due to the dramatic neurologicalpresentation).


CK7



CK20



TTF-1




Clinical data: F, 75, Ovarian Ca resected and chemo 8 years ago. Now drowsiness,

confusion. CT brain and abdomen: normal.

Slides: CSF MGG, CK; PM cerebellum, spinal cord.

Diagnosis: Meningeal carcinomatosis (c/w primary adeno Ca).

Comment: Meningeal carcinomatosis presents with non-specific diffuse CNS

dysfunction and is often not suspected. CSF is diagnostic but cavesampling bias. Often there is also a significant inflammatory reactionwhich may be misleading if there are only rare malignant cells.


CSF - MGG



CK - CSF



CK, cerebellum




Clinical data: M, 23, 6 weeks of somnolence, confusion, coma. MRI

hyperintensities hypothalamus and mesial temporal lobe.

Slides: (a) Amygdala HE, GFAP; (b) testes x2, PLAP.

Diagnosis: Paraneoplastic encephalitis (anti-MA2-positive) due to malignant

testicular intratubular germ cell tumour.

Comment: This is unlikely to be a real-life exam case. However, it emphasizes

the sometimes severe remote effects on the CNS of systemic, non-metastatic cancer. Strongly immunogenic Ôonconeuronal antigensÕare responsible for this, destroying the brain and keeping the cancerin check (it is often occult)


(a) Temporal lobe



(a) Temporal lobe, inflammation, gliosis (GFAP)



(b) Testis (neoplastic)



(b) Testis (neoplastic), PLAP




Clinical data: M, 62, weakness and sensory deficits at several spinal cord levels

developing over a few weeks. No diagnosis during life.

Slides: HE, LFB-CV, CD20.

Diagnosis: Intravascular B-cell lymphoma leading to multifocal ischemic lesions

of the spinal cord.

Comment: The CNS is often clinically affected by intravascular lymphoma due

to vasoocclusive disease. The diagnosis can be missed if patientsundergo biopsy during life. Virtually all intravascular lymphomas areof B-cell type. The myelin pallor of the dorsal columns in this case isprobably the result of the severe involvement of the dorsal roots.



CD20


Neuroinfection Ð Case 27

Clinical data: M, 39, HIV +ve for 9 years. 8 weeks confusion and occasional

seizures. Multiple lesions on MRI.

Slides: PM cerebellum, neocortex, basal ganglia (HE and toxoplasma

immunostain).

Diagnosis: HIV-associated CMV encephalitis, cryptococcosis, toxoplasmosis.

Comment: Note the bizarre CMV-transformed cells with nuclear virus (usually

close to the ventricular surface). The cryptococcus lesion is mainlynecrotic. There are both free as well as cystic forms of toxoplasma.As always, viable organisms are best appreciated at the edge of alesion.


CMV



TOXO (low-power, edge of lesion, cysts – arrows)



TOXO(immunostain labels both forms, cyst – arrow)




Clinical data: F, 23, drowsiness, mild fever, headaches. CT cortical nodule. Gap

year in Brazil.

Slides: CSF MGG, biopsy: cyst, brain parenchyma, HE.

Diagnosis: CSF: inflammatory with eosinophilia.

Biopsy: cysticercosis.

Comment: CSF eosinophilia is rare and may indicate a parasitic infection.

Biopsy: typical appearance of the cysticercus. The brain showsreactive changes Ð these are often the cause of the symptoms,particularly if the parasite dies or the cyst ruptures. Many cysticercimay remain ÔdormantÕ (clinically silent) throughout a patients life!


CSF



Reactive brain



Neurodegeneration Ð Case 29

Clinical data: F, 76, 7 months history of rapid-onset dementia and lethargy. Nil

else.

Slides: PM neocortex, cerebellum, HE and KG9 (anti PrP).

Diagnosis: Sporadic Creutzfeldt-Jakob disease, Codon 129 M/M.

Comment: This is the most common form of CJD. Note the patchy distribution

of spongiosis and PrP deposition. The pattern is diffuse / synaptic /perivacuolar and typical ÔKuruÕ type plaques are not present. In thisform of CJD the cerebrum is more affected than the cerebellum, andthere is no lymphoreticular infectivity (please compare with the nextcase (19)).



Clinical data: M, 31, 16 months of depression and irritability, followed by ataxia and

finally severe dementia.

Slides: PM neocortex, cerebellum, HE and KG9 (PrP) antibody.

Diagnosis: Variant Creutzfeldt-Jakob disease, Codon 129 M/M.

Comment: The ÔfloridÕ amyloid plaque with a corona of vacuoles is characteristic of

vCJD. The PrP load is usually high and shows plaque, diffuse andperivacuolar patterns. The cerebellum is severely affected and PrP ispresent systemically. So far all symptomatic vCJD patients are Codon129 MM, however 2004 saw the first MV case with systemic only PrPdeposition after a blood transfusion.


Cluster-plaques




Clinical data: M, 71, 10 years progressive slowness, stiffness, left-sided tremor.

Recently dementia.

Slides: PM midbrain, amygdala HE, alpha-synuclein.

Diagnosis: Lewy-body ParkinsonÕs disease with limbic/neocortical

involvement.

Comment: Lewy-bodies are intraneuronal eosinophilic inclusions composed

mainly of alpha-synuclein. They occur mainly in the nigra but alsoin limbic neocortical systems where they may correlate with PD-associated dementia.


Nigra with Lewy bodies - arrow



Nigra, alpha-synuclein positive Lewy body - arrow



Amygdala with Lewy bodies - arrows




Clinical data: M, 54, Trisomy 21.

Slides: Mesial temporal lobe, HE, beta-A4, phospho-tau (AT8).

Diagnosis: AlzheimerÕs disease pathology in Trisomy 21.

Comment The triplicated region of chromosome 21 in DownÕs syndrome

includes the gene for βAPP. ÔOverexpressionÕ of βAPP in thiscondition leads to βA4 amyloid plaque deposition and amyloidangiopathy. This is associated with formation of tau-containingneurofibrillary tangles. The neuropathology is essentially identical tothat of sporadic AlzheimerÕs disease.


Plaques



Plaques, bA4



Tangle



Tangle and neurites, AT8-tau



Neuroinflammation Ð Case 33

Clinical data: F, 53, long history of relapsing-remitting neurological illness

affecting brain, brainstem and spinal cord.Slides:

HE, LFB-CV, CD68, Neurofilament, Bielschowsky silver.Diagnosis:

Multiple sclerosis.Comment:

As illustrated in this section, MS plaques are often concentratedaround CSF spaces (ventricles). Note the sharp demarcation ofthe demyelinated area and the presence of myelin debris (bluegranules) within macrophages at the periphery of the lesion (LFB-CV stain). Note the relative preservation of neurons and axonswithin the demyelinated area (in an infarct both neuronal as wellas oligodendroglial/myelin components would be lost).



LFB-CV CD68

Note: pale demyelinatedarea corresponding tomacrophage-rich area.



LFB-CV CD68

myelin-ladenmacrophages


Neurotrauma Ð Case 34

Clinical data: M, 72, acute fracture of the spinal cord, survived 3 days.

Slides: HE, beta-APP, Bielschowsky silver.

Diagnosis: Acute traumatic axonal injury of the spinal cord.

Comment: Diffuse traumatic axonal injury may be the only histological manifestation

of a severe head / spinal injury. The earliest changes are dystrophicaxons that accumulate proteins that are axonally transported (antibodiesto beta-amyloid precurser protein (beta-APP) are the most commonlyused surrogate markers since these changes are rarely visible on H&E).The classical axonal retraction bulbs or axonal spheroids only becomeapparent after 12-36 hours of post-traumatic survival (note that this is nota fool proofed method to determine the time of the injury). The axonalspheroids are apparent on H&E and can be highlighted by silver stainsand immunocytochemical techniques.



Axonal retraction bulbs - arrows



Bielschowsky silver beta-APP immunocytochemistry


Muscle disease Ð Case 35

Clinical data: M, 66, known peripheral motor-sensory neuropathy.

Slides: HE, NADH.

Diagnosis: Muscle with longstanding denervation and reinnervation.

Comment: Note the increased fat and the relatively well-defined groups of

grossly atrophic fibres alternating with groups of hypertrophicfibres. The latter contain central ring-like structures and are calledÔtarget-fibresÕ; thought to be a sign of re-innervation. The groupatrophy in this example is severe, resulting in nuclear aggregatesand rounded fibres. Early atrophic fibres are often angulated.



Group atrophy / hypertrophy / increased fat



Target fibres

NADH

PAS



Clinical data: M, 52, progressive proximal lower and upper limb weakness.

Slides: HE, Gomori trichrome, succinate dehydrogenase (SDH),

cytochrome c oxidase (COX).Diagnosis:

Mitochondrial myopathy.Comment:

The mitochondrial cytopathies can manifest with a wide range ofneurological and non-neurological symptoms. Muscle biopsy is astandard diagnostic approach to these disorders. Not allmitochondrial cytopathies show the classical Ôragged-red fibresÕ(RRF) on Gomori stain; mitochondrial genetics may be necessary.The classical RRFÕs contain aggregated mitochondria, increasedSDH staining and absent COX staining, as in this example.



HE can often be unremarkable Gomori trichrome Ð ragged-red fibres



SDH COX


Miscellaneous CSFs Ð Case 37

Clinical data: F, 30, MS and psychosis.

Slides:CSF MGG, UCHL1, CD20.

Diagnosis: Lymphoplasmacytoid pleocytosis (reactive).

Comment:Most reactive CSF lymphocytic pleocytoses are T-cell

driven, most lymphoid neoplasms are of B-cell lineage.Acute MS may show a dramatic pleocytosis (generally,CSF cytology is NOT indicated in MS).


UCHL-1



CD20




Clinical data: M, 1, known AML M4, drowsy.

Slides: CSF MGG.

Diagnosis: Intrathecal dissemination of AML.

Comment: AML and other haematological neoplasms may disseminate via

CSF spaces, particularly in children. Limited phenotyping ispossible but often not necessary because the underlyinghaematooncological entity is already known.



Clinical data:M, 37, headaches, papilloedema.

Slides:CSF MGG, PAS, mucicarmine.

Diagnosis:Cryptococcus neoformans meningitis.

Comment:Not uncommon in severely immunosuppressed patients,

particularly AIDS. May be missed if the CSFinflammatory pleocytosis is significant. PAS/mucicarmineis best and shows the capsule of the yeast forms.



Clinical data: F, 35, breast CA.

Slides: CSF MGG.

Diagnosis: Meningeal carcinomatosis, c/w adenocarcinoma (breast)

primary.

Comment: This is a barn-door case. Note the bizarre vacuoles of the

carcinoma cells.

I hope all exam cases will be like this !

Good luck!


Note:The electronic imagescontained within this

document are for personaluse only!


© illustration, cellular pathology, oxford radcliffe … · enhancing frontal lesion ......

Documents