Australasian Division of the International Academy of Pathology Limited

ABN 73 008 593 815 37TH Annual Scientific Meeting

Darling Harbour Convention Centre, Sydney, Australia June 1-3, 2012

COMPANION MEETING NEUROPATHOLOGY

Bayside Room 102 Time: 11:15 – 1:00

Convenor: Dr Peter Robbins, PathWest, QEII Medical Centre, Perth,

WA

Lecture: Dr Michael Buckland, Royal Prince Alfred Hospital, Sydney, Case Presentations: Case 1: A/Prof. Michael Gonzales, Royal Melbourne Hospital, Melbourne Case 2: Dr Cesar M Salinas-La Rosa, St Vincent’s Hospital, Melbourne Lecture: Dr Peter Robbins, PathWest, QEII Medical Centre, Perth, WA

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Dr Michael Buckland  University of Sydney and Royal Prince Alfred Hospital

1p/19q deletion in oligodendrogliomas

EGFR gene amplification in glioblastomas

IDH mutations in diffuse gliomas

OVERVIEW

MGMT methylation in glioblastomas

BRAF duplication in pilocytic astrocytomas

BRAF mutations in other low grade gliomas

WHO 2007 Classification

Classification is exclusively based on MORPHOLOGY.

WHO 2007

LOSS of 1p &19q CHROMOSOME ARMS (1p19q loss)

Co‐deletion is very common in oligodendrogliomas:

up to 80% OII, and 70% OIII

%   f  i d  li40‐50%  of mixed oligoastrocytomas

More common in frontal, parietal, occipital lobes

Less common in temporal lobe, insula and diencephalon

1p/19q deletions in oligodendrogliomas

Caused by unbalanced translocationCaused by unbalanced translocation

Griffin et al. (2006) J. Neuropathol. Exp. Neurol.

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Clinical Implications of 1p19q loss

Radiation Therapy Oncology Group (RTOG) 9402 trial 286 patients with pure or mixed oligodendroglioma (III)

Approx. 50% had 1p/19q codeletion

Compared RT alone VS combined RT & Chemo (PCV)

FINDINGS FINDINGS: Median survival with codeletion = 8.7 years (Vs 2.7 yrs) regardless of treatment

Median survival for codeleted tumours treated with combination therapy = 14.7 years vs. 7.3 years for RT alone!

Isolated deletion of 1p or 19q had no prognostic benefit

CONCLUSION 1p/19 codeletion is prognostic

1p/19q codeletion is also predictive of response to chemo.

Testing Methods for 1p19q loss

Loss of heterozygosity (LOH) analysis (PCR‐based)

Fluorescent in‐situ hybridization (FISH)– performed on FFPE tissue sections

1p19q LOH Testing (i) DNA extracted from tumour cells and sample of patient’s peripheral blood

S ifi   i lli   i       d      Specific microsatellite regions on 1p and 19q are amplified by PCR in both samples

Analysis is only informative if the control blood sample is heterozygous for the allele 

1p19q LOH Testing: Microsatellite markers

= repeating sequences of 2‐6 base pairs of DNA

(eg CACACACACACACACACACACACACA)

Numerous scattered throughout genome

More prone to slippage during replication ‐> many have slightly different lengths in different individuals

Form basis of simple ‘genetic fingerprinting’

1p19q LOH Testing: Microsatellite markers

http://en.wikipedia.org/wiki/Microsatellite_(genetics)

1p19q LOH Testing• ADVANTAGES: 

• easily modified to look at multiple loci

• reduce risk of false positives due to partial loss

• DISADVANTAGES

• requires sample of patient’s blood

• sacrifices tissue from block

• time consuming: 2‐3 weeks for confirmed result 

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FLUORESCENCE IN SITU HYBRIDISATION (FISH)

1p36 / 1q25 probe set

19q13 / 19p13 probe set

1p loss and polysomy 1

CONCLUSION“The presence of polysomy in anaplastic oligodendrogliomas

with deletion of 1p/19q is a marker of earlier recurrence.”Oligodendroglioma WHO grade II

from WHO 2007 “Tumours of the CNS’

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Anaplastic Oligodendroglioma WHO grade III

from WHO 2007 “Tumours of the CNS’Diagnosis ???

Small cell glioblastoma 

(WHO grade IV)

‘Oligo‐like features’Oligo‐like features

• chicken‐wire vasculature 86%

• haloes  73%

• perineuronal satellitosis 58%

• microcalcifications  45%

Perry A et. al. Cancer. 2004;101(10):2318‐26.

Small Cell GBM vs Anaplastic Oligo (III)

Median survival times

AO (III) 5‐7 years (with 1p/19q loss)AO (III) 2‐3 years (without 1p/19q loss)

Small cell GBM (IV) 11 months

Small Cell GlioblastomasSmall Cell GlioblastomasEGFR amplification

EGFR amplification

Tumour 1p/19q loss EGFR amp

Oligodendroglioma III 70% ~1%

Small cell GBM <1% 70%

10 GBM 1‐5% 40%

MUTATIONS OF IDH1 and IDH2 Isocitrate dehydrogenase (IDH)

family of 3 enzymes involved in the Krebs cycle

involved in a number of metabolic pathways for cell d fdefence

IDH1 (cytosol)and IDH2 (mitochondrial) implicated in neoplasia

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MUTATION OF IDH1• 2008: mutations in IDH1 substrate binding site identified in secondary (sec) GBMs

• At least 70% diffuse As, Os, OAs and sec GBMs have IDH1 mutation; rare in primary GBMsIDH1 mutation; rare in primary GBMs.

• Defect in R132 residue (arginine) – substituted by histidine, serine, cysteine, glycine or leucine

• 90% are R132H type

• R132C type is especially characteristic of astrocytomas

MUTATION OF IDH2 Present in a small percentage of IDH1 negative tumours 

D f  i   di   i   id R   f  Defect in corresponding amino acid R127 of mitochondrial isoform

Especially characteristic of oligodendroglial tumours

Clinical Implications of IDH1 Mutations• Mutations have important role in neoplasia

• May explain age effect

• Mutations confer better overall survival: Mutations confer better overall survival: independently and any type (R132H or C)

• Rare mutated primary GBMs > non‐mutated primary GBMs

• Mutated sec GBMS> non‐mutated AIII

• Most paediatric high grade gliomas are non‐mutated

• Specificity of mutation: role in future therapies?

Testing for IDH Mutations Various

Immunohistochemistry for IDH1 (R132H)

New IDH1 (R132S) antibody also available

Direct sequencing

Other strategies (eg SNuPE, HRM)

IDH1 Mutation Immunohistochemistry• Routine IPX technique using monoclonal anti‐IDH1‐R132H antibody

• Clone H09 Dianova, Germany (direct import)

• Highly specific for tumour cells harbouring IDH1 mutation

• Detects 90% IDH1 mutated tumours (have IHD1 R132H type)

• 10% IDH1 mutated tumours are nonR132H type sequencing

• Some IDH1 neg tumours have IDH2 mutation sequencing

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Utility of IDH1 Immunohistochemistry:Diagnosis and prognosis

• Assess prognosis of diffuse gliomas

• Identify tumour in biopsies with few neoplastic cells

• Distinguish tumour from reactive gliosis (if positive)• Distinguish tumour from reactive gliosis (if positive)

• Detecting small amounts of residual or recurrent tumour after therapy

• Distinguishing morphologically similar tumours

IDH‐1

•Mimics: clear cell ependymoma vs oligodendroglioma

•Diffuse astrocytomas vs pilocytic astrocytoma or PXA

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Immunohistochemical Testing for IDH1(R132H) n=149(Tumour Type Total IDH1(R132H) +ve

Diffuse Astrocytoma (WHO2007 Grade II) 17 10 (59%)

Oligodendroglioma  (WHO2007 Grade II) 6 6 (100%)

Oligoastrocytoma (WHO2007 Grade II) 2 2 (100%)

Anaplastic Astrocytoma (WHO2007 Grade III) 4 3 (75%)

Anaplastic Oligodendroglioma (WHO2007 Grade III) 9 9 (100%)

Anaplastic Oligoastrocytoma (WHO2007 Grade III) 3 3 (100%)

Primary Adult GBM (WHO2007 Grade IV) 76 5 (6.6%)

Secondary GBM (WHO2007 Grade IV) 12 4 (33%)

Gliosarcoma (WHO2007 Grade IV) 2 0

GBM‐PNET (WHO2007 Grade IV) 4 1 (25%)

Pilocytic Astrocytoma (WHO2007 Grade I) 5 0

Neurocytoma (WHO2007 Grade II) 2 0

RGNT(WHO2007 Grade I) 1 0

SEGA(WHO2007 Grade I) 1 0

Ganglioglioma  (WHO2007 Grade I) 1 0

Reactive Glial Tissue 5 0

Total                  150 44 (29.5%)

DNA Sequencing for IDH1 and 2 

Mutations other than  R132H are Not Detected by Immunohistochemistry 

Sequencing was performed  in collaboration with Professor Ron Trent 

The RPA experience with IDH sequencing

R132GR132LR132S

MGMT gene silencing in gliomas

MGMT is a DNA repair enzyme (O6‐Methylguanine‐DNA methyltransferase)

Removes alkyl groups from O6 position of guanine in DNA.

Protects DNA from alkylating agent damage.

Temozolomide is an alkylating agent

The most reliable measure of MGMT gene silencing is promoter methylation

DNA Methylation Methyl group (‐CH3) added to cytosine residues

Occurs at cytosines in CG doublets (CpG methylation)

T A

methylation)

– half of all genes have “CpG islands” in their promoters 

When CpG methylation is dense, it is a reliable marker of silence

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Promoter Hypermethylation

“Epigenetic silencing of a normally active gene”AAAAAA

X

Normal Promoter

PromoterPromoterHypermethylation

The promoter is silent and densely methylated

Promoter hypermethylation is the functional equivalent of an inactivating mutation

Promoter hypermethylation is very common in tumours

Reduced or absent MGMT expression secondary to MGMT promoter methylation is common in glioblastomas, oligodendrogliomas and astrocytomas.

MGMT promoter methylation in gliomas

Tumours with MGMT methylation may respond better to chemotherapy with alkylating agents (eg Temozolamide).

We use bisulfite pyrosequencing to detect MGMT methylation

Normal Brain FFPE Sample

MGMT Pyrosequencing results

Brain Tumour FFPE Sample

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Nature. 2012 Feb 15;483(7390):479-83.Nature. 2012 Feb 15;483(7390):479-83.Nature. 2012 Feb 15;483(7390):479-83.Nature. 2012 Feb 15;483(7390):479-83.

Nature. 2012; 483(7390):479-83.

A relationship between IDH mutation and MGMT methylation?

BRAF in gliomas

BRAF alterations common in

Cerebellar pilocytic astrocytomas (BRAF duplication)

b ll l ( ) Extracerebellar pilocytic astrocytomas (BRAF V600E)

Pleomorphic Xanthoastrocytomas (BRAF V600E)

Gangliogliomas (BRAF V600E)

VERY RARE in other astrocytic neoplasms

Potential for DIAGNOSIS and THERAPY

Tandem duplication found in 66% of pilocytic astrocytomas (44 tested)

Almost all were typical cerebellar pilocytics

NO duplications found in other astrocytic neoplasms (244 tested)

RARE oligodendrogliomas/oligoastrocytomas had duplication (6/118)

All these were posterior fossa tumours with extremely long survival times

2Mb duplication

Leads to constitutive activation of BRAF

?Potential for therapy

Extra‐cerebellar pilocytic astrocytomas  9/9 (100%)

Pleomorphic Xanthoastrocytomas  42/64 (66%)

Gangliogliomas WHO grade II  14/87 (16%)

Anaplastic Gangliogliomas WHO grade III 3/6 (50%)

VERY RARE in other astrocytic neoplasms  (2‐3% of oligo’s, astro’s, GBM’s)

BRAF V600E Taqman Assay

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Sanger Sequencing     BRAF exon 15

Cell of origin

BRAF V600E mutation

Extracerebellarpilocytic astroPXA

li ligangliogliomas

MGMT promoter methylation

SUMMARY

There have been rapid advances in our understanding of the molecular underpinnings of gliomas in the last decade.

Distinct molecular lesions have relevance for:

Diagnosis

Prognosis

(Future) therapy

Case: 1 Presented by A/Professor Michael Gonzales. Department of Anatomical Pathology, Royal Melbourne Hospital, Parkville,Victoria. Clinical history: A 68 year old man presented with a two day history of blurring of his vision on a background of progressively worsening ataxia for the preceding two months. He had a past history of papillary carcinoma of thyroid, twenty years earlier for which he was treated with sub-total thyroidectomy followed by radiotherapy. Following this he became hypothyroid. A CT scan on admission showed a 1.5cm lesion in the left cerebellar hemisphere adjacent to the midline. The lesion was interpreted, radiologically as metastatic tumour. The patient underwent posterior fossa craniotomy. Tissue submitted for histopatholgy showed features of a low grade glial tumour. A post-operative MRI showed persistence of the lesion deep to the previous biopsy track. The patient underwent repeat sub-occipital craniotomy which yielded diagnostic tissue. The circulated section is from the second craniotomy. Diagnosis: Angiocentric glioma Angiocentric glioma seems to be the “best fit” diagnosis for the histopathological features in this case. Angiocentric glioma (AG) is an uncommon, epilepsy-associated, low grade glial neoplasm (WHO Grade 1) with a peak incidence in the second decade. (Wang et al.2005). It was placed in the category of “Other Neuroepithelial Tumours” in the 2007 iteration of the WHO Classification of Tumours of the Central Nervous System (Burger 2007). These tumours are usually cortically based, superficial lesions with high T2 weighted signal on MRI and minimal mass effect. There is one case report of AG involving thalamus and another involving quadrigeminal plate. The oldest patient with AG so far reported is 70 years (Preusser et al. 2007) A recurring component of the histopathology is aggregation of bipolar spindled cells around blood vessels, either in a peri-vascular pseudo-rosette like arrangement or as multi-layered cellular sleeves as seen in this case. In addition, there is frequently sub-pial aggregation of tumour cells. There may also be areas in which there is solid growth of tumour cells forming diffuse sheets of varying cellularity. The proportion of each of these patterns is widely variable but, at least, foci with the perivascular aggregation of tumour cells are always identified. Anaplastic features are lacking. A rare mitosis may be identified but microvascular proliferation and necrosis are absent. Immunohistochemistry shows strong staining for GFAP in tumour cells and the majority of angiocentric gliomas show peri-nuclear dot staining for EMA in

perivascular cells. Electron microscopy has shown intracellular lumena in these cells. These latter two features indicate ependymal differentiation. Proliferation indices are low (1% or less). Neither IDH1 or 2 mutations are detected. The cell of origin of AG remains in dispute. The EM demonstration of intracellular lumena and positive EMA staining have lead to the suggestion of an origin from tanycytic ependymal cells. Our finding of strong immunostaining for the stem cell marker, nestin, suggests that AG may arise from bipotential glial precursors. Molecular studies have shown alterations in a very small number of AG’s – loss of 6q24-5; gain of 11p11.2 2 which contains the locus of the protein-tyrosine phosphatase receptor type J (PTPRJ) gene (Preusser et al. 2007). A recent case series found features of malformation of cortical development (cortical dysplasia) adjacent to AG (Marburger & Prayson 2011), raising the possibility of AG being a maldevelopmental lesion. References: Wang M et al. 2005. Monomorphous angiocentric glioma: a distinctive epileptogenic neoplasm with features of infiltrating astrocytoma and ependymoma. J Neuropathol Exp Neurol 64(10); 875-881. Burger PC et al. 2007. Angiocentric Glioma. In Louis N et al (eds) WHO Classification of Tumours of The Central Nervous System. Pp92-93. Preusser M et al 2007. Angiocentric glioma. Report of clinico-pathologic and genetic findings in 8 cases. Am J Surg Pathol 31(11):1709-1718. Marburger T, Prayson R 2011 Angiocentric glioma. A clinico-pathologic review of 5 tumors with identification of associated cortical dysplasia.

NEUROPATHOLOGY COMPANION MEETING GANGLION CELL CONTAINING NEOPLASM OF THE SELLA TURCICA (AKA GANGLIOCYTOMA AND PITUITARY ADENOMA) Dr Cesar M. Salinas-La Rosa MD FRCPA St Vincent’s Hospital. Melbourne Ganglion cell-containing neoplasms in the sella turcica have been infrequently described. Histologically, they are mostly mixed tumour composed of adenomatous adenohypophyseal cells and ganglion cells. Most patients are middle female and up to ¾ of them are preoperatively diagnosed as having GH secreting pituitary adenoma (also described with LH, mixed LH/GH, null adenoma and rarely in ACTH adenoma)

Imaging and intraoperative inspection reveal no differences between gangliocytoma and pituitary adenoma.

A literature review of ganglion cell containing neoplasm in the sella turcica revealed few published reviews. These reviews include Towfighi et al. with 42 sellar lesions, Puchner et al. with 44 and Geddes et al with 8 lesions. In addition there is isolated case reports reported as collision tumours and/or rarities. Collectively, approximately less than a hundred sellar gangliocytomas have been reported since the initial description by Kyono in 1926. It is estimated that it represents less than 0.5% of tumours of the sella turcica. These unusual lesions have been variously referred to as "choristomas" (a confusing term often also applied to the unrelated granular cell tumours of the posterior pituitary), "ganglioneuromas,' and more recently "gangliocytoma”. The classification of pituitary tumours containing both adenomatous and neuronal components is controversial Although these tumours are genuine rarities without any known epidemiological importance, they do provide some interesting/controversial theories about tumorigenesis of pituitary adenomas. In Towfighi's well-documented series, 28 of the 32 patients in whom an adenoma was found were endocrinologically symptomatic: acromegaly (in a few cases with galactorrhea and amenorrhea) was seen in 19 patients, Cushing's in five, and three had galactorrhea/amenorrhea alone. One patient also had Zollinger-Ellison syndrome associated with MEN1. In four cases the adenoma was endocrinologically silent. The histogenesis of the ganglion cells in these lesions is the subject of debate and so far three hypotheses has been advanced.

The first is the proliferation of heterotopic intrasellar hypothalamic-like neurons gives rise to a gangliocytoma. The cells then stimulate adenohypophyseal proliferation by an endocrine or paracrine mechanism involving hypothalamic-releasing hormones

The second is that the gangliocytic component originates from neuronal differentiation within sparsely granulated growth hormone adenomas.

The third one, both the neuronal and adenomatous elements might originate from embryonal rests that contain common precursor cells showing intermediate features between neurons and adenohypophyseal cells. This assumption is in keeping with the common ectodermal embryonal origin of the adenohypophysis and infundibular region.

Immunohistochemical studies have shown the reactivity of adenohypophyseal cells for neuronal markers such as synaptophysin and NSE and the presence of adenohypophyseal hormones in the infundibular neurons. In addition in a review from Asa et al (1984), describing four intrasellar gangliocytomas causing acromegaly, noted "an intimate association between neurons and adenomatous GH cells"on electron microscopy. It is also well recognized that there is neuronal differentiation is in other neuroendocrine tumors, such as paraganglioma.

In the review articles the ganglion cell present in these lesions fell into three neuropathologically distinct groups (with 1 & 2 been the vast majority of cases): (1) admixed with a GH-producing adenoma, (2) apparently occurring as an isolated tumor, and (3) as a functioning lesion in the posterior pituitary The clinical significance of the finding of a probable neuronal differentiation in pituitary adenomas remains to be established. Nonetheless, in some some malignant neuroepithelial tumours such as neuroblastomas and medulloblastomas, neuronal differentiation is associated with a better prognosis (Hedborg et al 1995, Cai et al 2000; Yamaguchi et al 2007). Recent gene profiling studies of high grade gliomas have shown that a molecular subtype (proneuronal type) in a tumour displaying neural lineage mainly showed longer survival (Phillips et al 2006). Bibliography 1. Asa SL, Kovacs K, Horvath E, et al. Human fetal adenohypophysis. Electron microscopic and ultrastructural immunocytochemical analysis. Neuroendocrinology 1988;48:423 2. Asa SL, Scheithauer BW, Bilbao JM, et al. A case for hypothalamic acromegaly: a clinicopathological study of six patients with hypothalamic gangliocytomas producing growth-hormone-releasing factor. / Clin Endocrinol Metab 1984;58:796-803. 3.Baysefer A, Gezen F, Kayali H, Erdogan E, Timrkaynak E, Celasun B. Intrasellar gangliocytoma resembling pituitary adenoma. Minimally Invasive Neurosurgery 1997 ;40:107-9. 5. Burger PC, Scheithauer BW. Tumor-like lesions of maldevelopmental

or uncertain origin. In: Rosai J, ed. Tumors of the Central Nervous System. Washington, DC: Armed Forces Institute of Pathology, 1994. 6. Burger PC, Scheithauer BW. Tumors of paraganglionic tissue. In: Rosai J, ed. Tumors of the Central Nervous System. Washington, DC: Armed Forces Institute of Pathology, 1994. 7. Enzinger FM, Weiss SW. Paraganglioma. In: Enzinger 8. Puchner MJ, Ludecke DK, Saeger W, Riedel M, Asa SL. Gangliocytomas of the sellar region—a review. Exp Clin Endocrinol Diabetes 1995;103:129-*9. 9. Robertson DM, Hetherington RF. A case of ganglioneuroma arising in the pituitary fossa. J Neural Neurosurg Psychiatry 1964;27: 268-72. 10. Towfighi J, Salam MM, McLendon RE, Powers S, Page RB. Ganglion cell-containing tumors of the pituitary gland. Arch Pathol Lab Med 1996; 120:369-77.

Pseudotumours of the Central Nervous System Peter Robbins PathWest QEII Medical Centre Nedlands Western Australia A large number of non-neoplastic lesions involving the CNS and its coverings may, on occasion, mimic a neoplastic process. Although such ‘pseudotumours’ account for only a small proportion of neurosurgical biopsy specimens, they often prove diagnostically challenging, and errors in their interpretation can have profound clinical consequences. CNS pseudotumours represent a diverse group of conditions. Some are unique to the CNS, but some have systemic counterparts or form part of systemic conditions. Considered collectively, they have the potential to mimic virtually any form of CNS neoplasm. In their various guises, they may present as a localised ‘meningioma’-like dural mass, ‘pachymeningitis’ (diffuse meningeal thickening), single or multiple localised parenchymal lesions, or some combination of these. The following brief and selective discussion highlights morphological features useful in the recognition and diagnosis of some of these lesions, and will attempt to emphasise the critical need for careful correlation with clinical and laboratory data in formulating the final diagnosis. A large number of CNS infections may manifest as localised meningeal or parenchymal ‘pseudotumours’. Mycobacterial and fungal infections are perhaps the most common, but there are many other examples. Infective conditions will not be discussed in any detail, except to emphasise that an infective aetiology must be considered and excluded in virtually all inflammatory or necrotising CNS mass lesions, and particularly in the setting of immunosuppression. Identification of the pathogen(s) establishes the diagnosis, but the possibility of multiple pathologies must be borne in mind, particularly in the immunosuppressed. Tumefactive demyelinative lesion (TDL) Case 3 on DVD Primary demyelinative diseases represent a diverse group of disorders, characterised by myelin loss with relative sparing of axons. Biopsy is generally only performed when the clinical and / or radiological features are atypical, and some other pathological process (neoplastic or otherwise) is suspected or needs to be excluded. Without careful clinical and radiological correlation, it is possible that demyelinating central nervous system lesions be misinterpreted for pathological processes as diverse as infarction, infection or glioma. TDLs present as expansile, contrast enhancing, mass lesions. Clinically and radiologically, a single TDL may mimic glioma, and multiple lesions may suggest metastatic or infective processes. Metastatic carcinoma may particularly be suspected in cases of multifocal demyelinating disease associated with chemotherapy for colonic carcinoma. Tumefactive demyelination has also been described complicating immune reconstitution following highly active antiretroviral therapy. It is critical to avoid a misdiagnosis of ‘neoplasm’ in TDLs, as this will almost invariably lead to inappropriate and potentially dangerous therapy. Radiation therapy in particular dramatically exacerbates demyelinative conditions. Review of large

series of TDLs reveals a high rate of initial diagnostic error, with one study quoting an initial misdiagnosis rate of 31%. Awareness of the entity, careful attention paid to clinical and imaging findings, and knowledge of important microscopic featureswhich should always prompt consideration of demyelinating disease minimise the risk for diagnostic error. TDLs are bright in T2 weighted MRI and FLAIR sequences, may achieve a considerable size, and are associated with variable, though sometimes prominent, perilesional oedema. In demyelinative lesions a relatively characteristic, but not invariable, pattern of contrast enhancement may be observed. This pattern of a peripheral rim of ‘horseshoe shaped’ or ‘open ring’ enhancement differs from the rim-like or solid enhancing patterns of neoplastic processes. It should be noted however that rare examples of TDL may demonstrate irregular or diffuse enhancement. ‘Butterfly’ lesions are rare, but described. Microscopic features such as hypercellularity, pleomorphism and mitotic activity may erroneously suggest glioma, and their histiocyte rich character may be confused with infarction or infection. Microscopic features which should always prompt consideration of demyelinating disease include the presence of foamy histiocytes, particularly when present in large number or dispersed around blood vessels, prominent perivascular lymphoplasmacytic infiltrates, sharp lesional borders, pleomorphic astrogliosis, and Creutzfeld cells. A diagnostically important feature, the histiocytes have well defined cell borders, abundant granular or foamy cytoplasm, and are CD68 positive. Comparable histiocytic reactions virtually never occur in untreated glioma. At the time of intra-operative assessment, histiocytes may not be appreciated in frozen sections because their cytoplasmic membranes tend to be lost and nuclei may appear irregular and hyperchromatic. Smear preparations more reliably highlight their presence. The lymphocytes and plasma cells are polyclonal, and T cells predominate. GFAP aids in identifying the reactive nature of the gliosis. Demyelinating lesions usually have well defined borders, though this may not be appreciable in small biopsy samples. Once demyelination is considered, stains for myelin (e.g. Luxol Fast Blue) and axonal processes (e.g. Bodian or Neurofilament) will confirm selective myelin loss and relative axonal preservation. TDL are often misdiagnosed as glioma, particulary oligodendroglioma or mixed oligoastrocytoma. Hypercellular fields on biopsy from a cerebral ‘mass’ which contain cells with rounded nuclei and pale vacuolated (though not clear retracted) cytoplasm may mimic oligodendroglioma. The presence of admixed reactive and somewhat pleomorphihic astrocytes to this microscopic appearance may lead to an erroneous diagnosis of mixed oligo-astrocytoma. Importantly, low grade gliomas do not demonstrate contrast enhacement, and lack well defined lesional borders. Other macrophage rich non-neoplastic lesions potentially encountered in CNS biopsies include PML, cerebral infarct, and post steroid regression of NHL (see below). Progressive multifocal leukoencephalopathy [PML]. Case 4 on DVD PML is a uniformly fatal demyelinating disease caused by the JC virus [a member of the papova virus family]. PML usually occurs in the setting of immunosuppression,

most often in HIV/AIDS, but also in other situations of immunocompromise. Imaging studies reveal hypodense, non-enhancing white matter lesions, which are not associated with significant mass effect. Solitary lesions are rare, but described. The white matter lesions are small, discrete, and sometimes rounded, and are seen particularly at the gray white matter junction, often within parietal and occipital lobes. The clinical differential diagnosis often includes toxoplasmsosis and NHL, and, if an imunosuppressed state is not immediately recognised (as is sometimes the case), glioma. PCR based detection of JC virus DNA in CSF now often precludes the need for biopsy. Microscopic examination reveals patchy demyelination. The biopsy appearances are similar to MS, but lesions of PML are not as histiocyte rich and tend to demonstrate less perivascular inflammation (though this is not the case in immune reconstitution syndromes following highly active antiretroviral therapy). Characteristic are enlarged pleomorphic and bizarre astrocytes, and oligodendrocytes with ground glass nuclei containing basophilic inclusions. Such viral inclusions are often best seen at the periphery of the lesions. The astrocytic aytpia may reinforce an erroneous impression of glioma. There is often strong p53 immunopositivity, and in large lesions necrosis may be present. In biopsy material, diagnosis may be confirmed with IHC or ISH, and viral particles can be identified ultrastructurally. Cerebral infarcts are usually not subject to biopsy, except in cases with atypical clinical or radiological findings. Deeply situated arterial infarcts and venous infarcts are examples. At particular phases e.g. approximately 7 days following the initial vascular insult, the imaging characteristics of an infarct (a low density lesion with some mass effect, and ring enhancement), may be confused with glioma. If sampled at particular phases in their evolution, infarcts may also have potentially confusing microscopic appearances. The cellular and histiocyte rich patterns of an infarct must be distinguished from both glioma and demyelinating disease. As in demyelinating disease, both perivascular concentration of the foamy histiocytes and some mitotic activity may be evident. Necrotic parenchyma is not invariably present; the histiocytes may infiltrate viable tissue, and there may be no cortical representation to assess ischaemic neuronal changes. Reactive and proliferative vascular changes in an infarct may heighten the resemblance to glioma. Immunostaining for CD68 and GFAP usually resolves the diagnosis. Foamy histiocytes, perivascular lymphoplasmacytic infiltrates and gliosis may also be observed in areas of CNS lymphoma regression, particularly after pre-operative treatment with corticosteroid leading to regression (‘vanishing’ lesions). Granular cell alteration in astrocytic neoplasms also needs to be distinguished from the histiocyte rich character of TDL and infarcts. GFAP positivity, nuclear atypia, and transition to more typical areas of astrocytoma usually resolves this diagnosis. “Inflammatory Pseudotumour” (IPST) / Inflammatory myofibroblastic tumour (IMT) Case 5 on DVD Broadly speaking, ‘inflammatory pseudotumour’ refers to a group of conditions characterised by a tumefactive proliferation of myofibroblastic spindle cells accompanied by lymphoplasmacytic infiltrates. First recognised in the lung, and increasingly in extrapulmonary sites including the CNS, these lesions have variously been referred to as ‘plasma cell granuloma’, inflammatory myofibroblastic tumour

(IMT), ‘inflammatory fibromyxoid tumor’, and ‘inflammatory fibrosarcoma’ (amongst others). Initially regarded as a post inflammatory and reactive process, these conditions are now recognised to range from the benign and self-limiting, to neoplasms with the capacity for locally aggressive growth, recurrence and, on rare occasion, malignant behaviour. A subset of ‘inflammatory pseudotumours’ appears to be reactive and related to various infectious agents, including Epstein-Barr virus and human herpesvirus-8. Hepatic and splenic examples appear to represent EBV-related follicular dendritic cell proliferations / neoplasms, though EBV does not appear to play a major role in the pathogenesis of IPST at other sites. Other ‘inflammatory pseudotumours’ appear to be reparative in character; - examples include the clinically benign myofibroblastic proliferations resembling nodular fasciitis in sites such as the lower urogenital tract. Inflammatory myofibroblastic tumour (IMT), previously regarded as synonymous with IPST, represents a neoplastic myofibroblastic proliferation. The clinical behaviour of this group includes the capacity for locally aggressive growth, vascular invasion, and rarely malignant transformation. Some IMTs have clonal rearrangements of the anaplastic lymphoma kinase (ALK) gene (2p23) and expression of ALK protein which can be detected immunohistochemically. ALK positivity is reported with variable frequency. Malignant transformation is rare, and is manifest morphologically by the emergence of a mitotically active and pleomorphic population of polygonal cells. It is unclear whether lesions which are identical morphologically in every other respect to ALK+ IMT, but which lack detectable ALK alterations, should be regarded as separate and distinct lesions. As in other sites, CNS IPSTs described in the literature probably represent a spectrum of conditions, including both neoplastic and non-neoplastic processes, rather than a single entity, and this heterogeneity should be borne in mind when reviewing the literature. None the less, in general terms, involvement of the CNS by IPST/IMT, either primarily or by extension from adjacent structures, is rare. Primary sites of origin include the meninges, ventricles and cerebral parenchyma. The majority are solitary lesions, which may present at virtually any age. Occasional examples have concurrent pulmonary and CNS lesions. Symptoms at presentation are site dependent, but are usually those of a mass lesion, with headache and seizures being the most common. A significant proportion of IPST arise in the region of the sella and parasellar structures, where they are often associated with visual and hormonal disturbances. A small proportion is associated with systemic symptoms. The histological appearances are polymorphous - a myofibroblastic spindle cell proliferation and an accompanying inflammatory infiltrate are the principle constituents. Three basic histological patterns of extrapulmonary IMT were described by Coffin et al. These include a myxoid vascular pattern with inflammatory areas resembling nodular fasciitis or granulation tissue, a compact spindle cell pattern with intermingled inflammatory cells resembling fibrous histiocytoma, and a hypocellular fibrous pattern with dense plate-like collagen resembling a scar or fibromatosis. The relative proportions of these various patterns may vary from one example to another, and also within the same lesion. The inflammatory components of plasma cells, lymphocytes and eosinophils are haphazardly scattered throughout the stroma. Plasma

cells often predominate in the infiltrate, but are polyclonal in nature. In general, necrosis, granulomata and abscesses are not seen in IMT. Irregular stromal calcifications and metaplastic bone may rarely be present. In keeping with their myofibroblastic character, the lesional cells of IMT are usually vimentin positive, and often express muscle specific and smooth muscle actins. Desmin positivity is less frequent. Focal cytokeratin may be observed, and CD68 positivity is not uncommon. Immunophenotypic studies reveal a T-cell predominant lymphoid population and polyclonal plasma cells. IMT is uncommon in the CNS, and therefore is prone to misdiagnosis. The histological differential diagnosis is broad, and includes both reactive and neoplastic conditions. Depending on the specific site of involvement, and the predominant microscopic patterns evident, the differential may include a entities such as plasmacytoma, meningiomas with extensive lymphoplasmacytic infiltrates, infective and autoimmune disorders, and Langerhan’s cell histiocytosis. Lymphoplasmacytic meningioma is characterised by pronounced lymphoplasmacytic infiltrates, which may be so dense as to obscure the underlying meningothelial cells. This subtype of meningioma may prove diagnostically challenging if the underlying meningioma is not recognised. Focal EMA positivity may be observed within the plasma cell population, or within entrapped arachnoid, but IMT lacks features of meningioma or the EMA positivity common to meningiomas. A prominent lymphoplasmacytic infiltrate may also be present in chordoid meningioma, a feature more typically seen in paediatric examples. Adding to the potential confusion, some lymphoplasmacytic meningiomas and paediatric chordoid meningiomas may be associated with various systemic and haematological abnormalities. The distinction between IMT and spindle cell meningeal neoplasms of various types e.g. fibroblastic meningioma, SFT, smooth muscle tumours, meningeal sarcomas, etc, is usually straightforward. These meningeal neoplasms typically lack the marked inflammatory component of IMT. Further, the myofibroblastic spindle cell component of IMT has a relatively distinctive appearance and myofibroblastic immunophenotype, and lacks expression of markers such as EMA and CD34. Areas with pronounced lymphoplasmacytic infiltrates may raise the possibility of lymphoproliferative disorders, which may present in, or secondarily involve, the CNS. Possible confusion may arise with non-Hodgkins lymphoma, plasmacytoma, Hodgkin disease and Castleman’s disease. High grade or large cell forms of lymphoma can usually be readily excluded on microscopic examination. The distinction between plasmacytoma and IMT is usually straightforward. Plasmacytomas have monotonous microscopic appearances, lack the heterogeneity of IMT, and demonstrate light chain restriction. The lymphoid populations in IMT are predominantly small and mature, consist chiefly of T-cells, and tend to be haphazardly scattered throughout the stroma. Plasma cells often predominate, but are polyclonal in nature. Differentiation from low-grade lymphoma may be assisted by immunophenotypic and / or molecular studies in difficult cases. The diagnosis of Hodgkin's disease rests upon the identification of Reed-Sternberg cells within an appropriate cellular milieu, which includes polytypic T and B lymphocytes as well as variable numbers of eosinophils. Although uncommon, pseudotumour formation may complicate, or be the presenting manifestation, of CNS vasculitis, be it either primary i.e. where the CNS is the sole or

predominantly affected organ, or secondary, where the CNS involvement occurs in association with a systemic process. Primary angiitis of the CNS (PACNS) Case 8 on DVD may, on occasion, present as a cerebral mass lesion. PACNS is a rare leptomeningeal and cortical vasculitic disease, principally affecting small to medium sized arteries and arterioles, and less frequently veins and venules. Involvement of extracranial blood vessels occurs only rarely. Presentation with a mass lesion is reported in 15% of pathologically documented cases of PACNS. The cerebral angiogram may show multifocal, segmental stenosis or irregularity of small and medium-sized meningeal and parenchymal blood vessels, often with ‘beading’ or aneurysmal changes. The neuroimaging appearances of PACNS related mass lesions are generally not as specific, though angiographic examination reveals abnormalities in the majority of cases. Histologically, PACNS may be granulomatous, necrotizing, or lymphocytic in character, and mixed morphologic types often occur. In a sizeable proportion of PACNS mass lesions, the vasculitis has leukocytoclastic features. Large- and small-vessel thrombosis is common. Acute lesions frequently coexist with healing or healed lesions. The vasculitis is focal and segmental in distribution, and a negative biopsy, therefore, does not rule out the disease. PACNS must be distinguished from ‘secondary’ CNS vasculitis, and vasculitis ‘mimics’. Of the systemic vasculidities, CNS involvement most commonly occurs in polyarteritis nodosa, Behcet's symdrome, Wegener’s Granulomatosis (WG), and Churg-Strauss syndrome (CSS). Various forms of CNS involvement can also occur in SLE and Sjorgen’s syndrome. Secondary CNS vasculitis may complicate infections (Herpes Zoster, HIV etc), and has also been reported in association with Hodgkin disease (HD) and non-Hodgkin lymphoma (NHL). Diagnosis is usually not difficult in these situations, because CNS manifestations rarely occur when systemic signs of disease are absent or subtle. Wherever possible, in cases of suspected CNS vasculitis, biopsies should be directed to a radiographically abnormal area, particularly if enhancement is evident, as this improves diagnostic sensitivity. Sampling of both meninges and cortex may increase diagnostic yield, as vasculitis may affect either site in isolation. Sampling of the basal meninges is important when chronic infections and / or sarcoidosis are considered in the differential diagnosis. Morphological mimics of CNS vasculitis which may present with mass lesions include cerebral amyloid angiopathy (CAA) and angiocentric immunoproliferative disorders (AIL). Cerebral amyloid angiopathy (CAA) Case 7 on DVD CAA is a disease of the elderly, which most commonly presents with lobar or subarachnoid haemorrhage or altered mental state. Severe CAA may be associated with an inflammatory and granulomatous vascular reaction, and this combination of vascular amyloid and ‘vasculitis’ may rarely present as a pseudotumour. Rather than representing a primary vasculitis, it is now generally accepted the inflammatory and granulomatous changes are a secondary reaction to vessel injury associated with the amyloid deposition. Special stains (Congo red) and immunocytochemistry for β-A4

amyloid highlight the vascular amyloid, which may also be identified as ingested material within giant cells, and often reveals other Alzheimer related changes. Small to medium sized arteries and arterioles of the meninges and cortex are principally affected. The vessels often demonstrate severe vasculopathic changes, including thrombosis and luminal occlusion, fibrinoid necrosis, onion-skinning, double-barrelling and/or microaneurysms. Cerebral infarcts of varying age and and intracerebral haemorrhages ranging from massive to petechial complicate the vascular amyloid deposition. A combination of ischaemic changes secondary to vascular compromise, haemorrhage and oedema is believed to account for the parenchymal pathology which uncommonly leads to presentation with a mass lesion. Most forms of AIL are angiocentric B-cell lymphomas associated with EBV infection. AIL usually demonstrates EBER positive atypical B cells in a polymorphous background. The diagnosis can, on occasion, be difficult, particularly in small biopsies or in cases in which the large atypical neoplastic B-cell population is sparse or difficult to identify. Although uncommon, CNS pseudotumour formation may also complicate a number of collagen vascular diseases, characterised by ‘vasculitis and granulomatosis’ e.g. Wegener’s granulomatosis (WG). In most such cases, systemic disease is present ab initio, and the diagnosis can be established on the basis of clinical and laboratory abnormalities. Biopsies are generally only performed when the CNS manifestations occur at presentation, when systemic signs of disease are absent or subtle, or when infective complications of immunosuppressive therapy need to be excluded. Wegener’s granulomatosis (WG) Case 6 on DVD Three patterns of CNS involvement in WG are recognised. The first is contiguous involvement of the brain by granulomatous lesions arising in the paranasal sinuses. The second is the development of vasculitis, leading to complications such as intracranial, subarachnoid or subdural haemorrhage, and arterial and venous thrombosis. The third, and least common, form of CNS involvement is the formation of individual or multiple granulomatous lesions, either in the cerebral parenchyma, cranial nerves, or meninges. The diagnosis of WG rests on a constellation of clinical features, histological changes, ANCA studies, and the exclusion of infection. In almost all cases of WG, no single laboratory test or radiological finding can confirm the diagnosis. The biopsy findings in WG vary greatly and are influenced by the type and size of tissue sample. The classical microscopic findings of WG, a confluent or serpiginous geographic pattern of tissue necrosis and vasculitis, occurs most often in the pulmonary parenchyma, and can usually only be appreciated in large biopsy (e.g. open lung) specimens. Small biopsy samples may only show non-specific inflammatory changes. The pattern of necrosis in WG is typically that of large geographic areas of involvement. Micro-abscesses and focal necrotising lesions may also be found. Well-formed sarcoidal granulomata are not a typical feature, more frequently there are randomly dispersed multinucleated giant cells. The vasculitis has a destructive and leukocytolytic character, and involves small to medium sized vessels (arteries, capillaries, and veins).

Meningeal involvement in WG is rare, particularly as a presenting complaint, and usually manifests as headache or cranial nerve abnormalities. MRI is the most sensitive method for detecting meningeal involvement in WG, but the findings (meningeal thickening with enhancement following gadolinium) are not specific, and may be seen in a number of other conditions including infections, neurosarcoidosis, hypertrophic pachymeningitis and malignancies. CSF findings are often non-specific and meningeal biopsy may be necessary for definitive diagnosis, especially to distinguish infective complications of immunosuppressive therapy, including cryptococal or tuberculous meningitis, from aseptic granulomatous meningeal involvement. Geographic areas of necrosis may also occur in rheumatoid nodules. Patients with Rheumatoid arthritis may develop neurological complications through a variety of mechanisms. Tissue damage may result from structural / anatomical alterations, either from direct compression of neural tissue or vascular compromise. The three characteristic findings in inflammatory Rheumatoid CNS disease (i.e. non-structural disorders) are rheumatoid nodules, pachymeningitis or leptomeningitis, and vasculitis, either singly or in combination. They are typically associated with long-standing severe nodular, seropositive disease, but can occur in the absence of active synovitis, extracranial vasculitis and nodules. Morphological features suggestive of collagen vascular disease rather than infection include serpiginous rather than rounded areas of necrosis, the absence of well-formed granulomata, and the presence of vasculitis in parenchyma distant from areas of marked necrosis and inflammation. Involvement of the CNS occurs in a relatively small proportion of patients with sarcoidosis. Isolated neurosarcoidosis i.e. CNS disease without signs of systemic disease, is exceptionally rare. Intracranial sarcoid manifests as nodular or diffuse leptomeningeal thickening and extra- or intra-axial parenchymal lesions, and may mimic various forms of meningitis, and mass lesions such as meningioma, lymphoma and glioma based on imaging. Intracranial sarcoid may involve any part of the brain, but has a predilection for the basal meninges. Cranial nerve involvement is the most common symptom. Only exceptional examples of neurosarcoid are tumefactive, and of these, a dural-based meningioma-like lesion is the most common. The clinical presentation and imaging findings of neurosarcoidosis are relatively non-specific, and the clinical diagnosis is often difficult, particularly if systemic signs of disease are subtle or absent. No reliable diagnostic test exists in situations where the CNS involvement is the first or only manifestation of disease, and isolated neurosarcoid may be impossible to distinguish from tuberculosis, primary CNS granulomatous angiitis, and other ‘pathogen free’ granulomatous CNS disorders. The classical histological findings of sarcoid i.e. non-necrotising granulomata and granulomatous vasculitis, are not specific or diagnostic. Central necrosis may rarely occur within sarcoid granulomata, and vessels associated with the granulomatous inflammatory process may demonstrate fibrinoid necrosis with thrombosis, thus increasing the resemblance to other granulomatous conditions in the CNS. The diagnosis of sarcoidosis is one of exclusion, which should be made in

clinicopathological context, and after other causes of granulomatous inflammation have been excluded by special stains, and ideally, culture. Idiopathic hypertrophic pachymeningitis (IHP) is a rare and somewhat ill-defined condition, characterised by extensive fibrosis and inflammation of intracranial or spinal dura. There is usually no deep parenchymal or systemic involvement. These lesions typically cause progressive cranial nerve palsies, headaches, and cerebellar dysfunction. They occur in all age groups; the peak incidence is in the sixth decade. Hypertrophic cranial pachymeningitis is initially responsive to steroid therapy, but in most cases it recurs or progresses despite treatment. Surgical excision is occasionally necessary to alleviate mass effect. The long-term outcome is uncertain for most patients, but progressive disease is usually fatal. Dural biopsy is mandatory to confirm the diagnosis, which is essentially one of exclusion. The meningeal inflammation may occasionally be granulomatous in character, but necrosis is rare. The process is best identified on MRI, but the imaging characteristics (meningeal thickening with enhancement following gadolinium) are not specific, and may be seen in several other conditions, including infection, malignancy, and sarcoidosis. It is now believed that at least a subset of the cases historically diagnosed as idiopathic hypertrophic pachymeningitis represent CNS manifestations of the recently described spectrum of IgG4-related sclerosing disease. These sclerosing fibroinflammatory lesions, first identified in the pancreas, may involve many sites, and have a variable association with raised serum IgG4 levels. The typical histological features of IgG4-related disease including lymphoplasmacytic inflammation, fibrosis, and phlebitis. The evaluation of IgG4+ plasma cells and the ratio of IgG4+/IgG+ plasma cells and the presence of obstructive phlebitis may be diagnostically useful, and in the differential diagnosis of IMT and IgG4-related sclerosing disease. The phlebitis may however prove difficult to identify, particularly in small biopsies. It is believed that IgG4 does not play an important role in the pathogenesis of IMT. A number of other non-infective granulomatous processes may present as CNS pseudotumours. Many (e.g. xanthogranulomas of choroid plexus, cholesterol granulomas, and foreign body granulomas) are uncommon in surgical biopsy material, but usually present little diagnostic difficulty. Others are rare, but when biopsied, prove diagnostically challenging. In the suprasellar region, chronic inflammatory and granulomatous reactions may be observed in association with germinomas, and the possibility of a contiguous germinoma should always be considered in this setting. Castleman's disease is a rare lymphoproliferative disorder, of uncertain aetiology, which may manifest as a localised tumor-like mass or as a systemic disorder. Peripheral neuropathy is not an uncommon neurological complication, but CNS involvement is exceptionally rare. The majority of such cases present as a solitary meningioma-like mass, and are more frequently of the hyaline-vascular subtype, characterised by follicles having regressed germinal centres and concentrically expanded ‘onion skin’ mantles, radially penetrating vesels, and prominent interfollicular vascularity with perivascular hyaline material. The process is polyclonal, and must be distinguished from meningeal NHL.

Sinus histiocytosis with massive lymphadenopathy (SHML), is a rare benign histiocytic proliferative disorder which usually presents with bilateral painless cervical lymphadenopathy. CNS involvement is rare, and usually presents clinically and radiologically as a "meningioma’. Rare parenchymal examples are described. Histological and immunohistochemical confirmation is essential for diagnosis. The histiocytes have bland nuclei, abundant cytoplasm and indistinct cell borders. Emperipolesis, usually of lymphocytes, is characteristic. The cells are S-100 protein and CD68 positive, and CD-1a negative. SHML may also exhibit atypical histologic features. CNS SHML may be misdiagnosed as a nonspecific inflammatory process because CNS disease, as with other extra-nodal locations may demonstrate atypical histologic features, e.g. the histiocytic component and emperipolesis may be obscured by other inflammatory cells. Erdheim-Chester disease (ECD) is a rare systemic histiocytic disease of unknown aetiology, characterised by xanthogranulomatous infiltrates, and radiologically by symmetrical osteosclerosis of long bones. The diagnosis relies on the association of specific radiologic and histologic findings. Intracranial involvement is rare. The most frequent CNS manifestations are diabetes insipidus, cerebellar syndromes, orbital lesions, and extra-axial masses involving the dura. ECD may be confused with LCH, as it may share the same clinical (exophthalmos, diabetes insipidus) or radiologic (osteolytic lesions) findings, but the histiocytic infiltrate lacks the features of LCH (S-100 protein and CD1a negative, no Birbeck granules). The most common manifestation of CNS Langerhans’ Cell Histiocytosis (LCH) is involvement of the hypothalamic-pituitary system. Involvement of other CNS sites tends to be rare, even in multisystem disease. Lesions may be solitary or multiple, and extend from adjacent bone lesions, or arise ‘primarily’ in the meninges, cerebral parenchyma or choroid plexus. There are varied proportions of Langerhan’s cells, eosinophils and other inflammatory cells in a background in which necrosis, sclerosis and vascular inflammation may be apparent. Diagnosis rests on the recognition of Langerhan’s cells, which have irregular reniform nuclei with longitudinal grooving or indentation, are CD1a and S100 protein positive, and contain Birbeck granules on ultrastructural examination. Neoplasms and tumour-like conditions of the pineal gland and pineal region are a diverse group of entities. Collectively they are relatively uncommon, and often pose considerable diagnostic difficulty for the surgical pathologist, particularly when small or stereotactic biopsy specimens are studied. Glial cysts of the pineal gland Case 9 on DVD are benign and mostly asymptomatic lesions found incidentally on neuroimaging studies or at autopsy examinations. In rare cases, they may become symptomatic and require surgical intervention. These lesions are often misdiagnosed as a pineocytoma or pilocytic astrocytoma, and it is critical the pathologist accurately recognise the non-neoplastic nature of this lesion, and not confuse it with a neoplasm of the pineal region. Symptomatic cysts vary in size from 7 mm to 45 mm, whereas asymptomatic cysts are usually less than 10 mm in diameter, although the relationship between cyst size and the onset of symptoms is not always clear cut. In most cases, symptoms and signs relate to raised intracranial pressure, hydrocephalus, neuroophthalmologic

dysfunction, brainstem and cerebellar compression, and changes in mental state. Severe headache, diplopia, or Parinaud syndrome may occur as a result of pineal apoplexy due to intracystic haemorrhage. Sudden death may very rarely occur. The MR appearance of benign pineal cysts is variable, ranging from that of an uncomplicated cystic mass to a mass associated with hemorrhage, enhancement, or hydrocephalus. This variability may make them indistinguishable from other pineal-region tumors. The cysts are unilocular, and the wall has a trilaminar structure. The inner lining is astrocytic and fibrillary in character, and may contain Rosenthal fibres, eosinophilic granular bodies and / or haemosiderophages. External to this is a variably calcified layer of pineal parenchymal tissue, which is often somewhat disordered and disorganized, and external to this is a thin and often incomplete layer of fibrous tissue. In intact and well oriented excision specimens the diagnosis is usually straightforward. Misdiagnosis however is not infrequent, - errors may occur if the histological samples are small or poorly oriented and particularly if careful attention is not paid to the neuroimaging studies. When seen in small fragments, or if cut enface, the compressed and distorted layer of pineal tissue may be erroneously interpreted as a pineal parenchymal tumour. Similarly, the glial lining, with its combination of reactive astrocytic atypia, Rosenthal fibres and eosinophilic granular bodies may lead to confusion with pilocytic and/or fibrillary astrocytoma. The distorted pineal parenchyma lacks pineocytomatous rosettes, and contains scattered calcification. When piloid in character, the glial lining lacks the classical biphasic architecture (particularly the microcystic pattern) of pilocytic astrocytoma, and its characteristic hyalinised vessels. In conclusion, IPST of the CNS are uncommon, and often prove diagnostically challenging. Depending on the site of involvement and the histological features, the differential diagnosis may be broad and includes both reactive and neoplastic conditions. Many have relatively non-specific clinical and radiological features, and the nature of the disease process is often unsuspected prior to biopsy. Appropriate specimen triage and handling is critical to enable appropriate laboratory studies, and in particular, microbiological assessment. Careful correlation with clinical, laboratory and radiographic data is essential for accurate diagnosis, but in a proportion of cases, precise classification of the process may be impossible. It is critical to avoid a misdiagnosis of ‘neoplasm’, as this may lead to inappropriate and potentially dangerous therapy. References: General Kleinman GM, Miller DC. Pseudoneoplastic Lesions of the Central Nervous System. In: Wick MR, Humphrey PA, Ritter JH, eds. Pathology of Pseudoneoplastic Lesions. Philadelphia: Lippincott Raven, 1997; 25-68. Burger PC, Scheithauer BW, Vogel FS. Surgical Pathology of the Nervous System and its Coverings, 4th edn. Philadelphia:Churchill Livingstone, 2002. Tumefactive Demyelinating Lesions

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