The past: LEAT-Study

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Long-term Epilepsy associated Tumors(LEAT)

H. Urbach

Dept. of Neuroradiology, [email protected]

LEAT• Long-term Epilepsy-associated tumors = tumor subtype associated with

long-lasting epilepsy *

• GangliogliomaDNTpilocytic astrocytomaPXA

astrocytoma WHO °II, IIIoligodendroglioma WHO °II, III

isomorphic astrocytoma (Blümcke et al. 2004)

ANET (Wang et al. 2005, Lelloch-Tabiana et al. 2005)

Multinodular and Vacuolating Neuronal Tumor (Huse et al. 2013)

Polymorphous low-grade neuroepithelial tumor of the young (Huse et al. 2017)

Papillary glioneuronal tumor (Kim and Suh 1997)

Glioneuronal tumor with neuropil islands (Teo et al. 1999)

* Luyken C, Blumcke I, Fimmers R, Urbach H, Elger CE, Wiestler OD, Schramm J. The spectrum of long-term epilepsy-associated tumors: long-term seizure and tumor outcome and neurosurgical aspects. Epilepsia 2003; 44: 822–830.

Ganglioglioma DNT PXA ANET

PGNT isomorphic astrocytoma MNVT Ependymoma

The past: LEAT-Study

Blümcke I et al. A neuropathology based approach to epilepsy surgery in brain tumors. Acta Neuropathol 2014;

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Blümcke I et al. A neuropathology based approach to epilepsy surgery in brain tumors. Acta Neuropath 2014;Thom M et al. Long-term epilepsy-associated tumors. Brain Pathol 2012;22:350-79

8 international LEAT-series (n=2055) Ganglioglioma and DNT most common tumors, but relative frequencies from 7-70%

isomorphic astrocytoma

…. other LEAT:Pilocytic astrocytoma (PA)Papillary Glioneuronal Tumor (PGNT) Multinodular and Vacuolating Neuronal Tumor of the Cerebrum (MVNT)Glioneuronal Tumor with Neuropil Islands (GTNI)Cortical ependymoma….

Louis DN et al. The 2016 World Health Organization Classification of Tumors of the Central NervousSystem: a summary. Acta Neuropathol 2016;131:803–820

Capper D et al. DNA methylation-based classification of central nervous system tumours. Nature 2018;

Ganglioglioma: MRI

• Cortical/ subcortical location

• Cortical/ subcortical cyst(s)

• FLAIR/ T2-hyperintense cortical/ subcortical lesion parts

• Contrast enhancement: 1/3 of cases

• Calcification(s): 1/3 of cases

• No edema

• Others: exophytic growth, bone remodelling, …

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S.R., 31.10.93, 28.9.12

Ganglioglioma WHO I Ganglioglioma

• WHO I ≈ 95%, WHO II, WHO III ≈ 5%

• prognostic parameters for a poor outcome 1:extratemporal location male gender age at surgery <40 years a history without epilepsy incomplete tumor resection gemistocytic cell component

1 Majores M et al. Tumor recurrence and malignant progression of gangliomas. Cancer 2008;113:3355-63

Ganglioglioma: transcription analysis

97 Gangliogliomas with 14 recurring tumorsrecurring tumors: BRAF V600E-mutation

Delev D et al. Long-term epilepsy-associated tumors: transcriptional signatures reflect clinical course. Scientific Reports 2020;10:96

LEATs: transcription analysis


43 LEATs 4 Cluster, all IDH-wt

+ 2 PXAs

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Ganglioglioma WHO IH&E

H&E

GFAP CD34

?

Ganglioglioma WHO II (2005) → Ganglioglioma WHO III

BRAF Exon 15 V600E-mutation 1

1 Schindler et al. Acta Neuropathol. 2011;121:397-405

LEATs: transcription analysis


43 LEATs 4 Cluster, all IDH-wt

+ 2 PXAs

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DNT: MRI

• single or multipe cysts ≈ glioneuronal element- round or perpendicular to the cortical surface- ring-like contrast enhancement within the cyst,

which may change on f/u- small cysts in the vincinity separated by normal parenchyma

• simple variants: glioneuronal element only

• complex variants: calcificationsgrowth and tumor bleedings

Campos AR et al. Neuroradiology 2009;51:433-43

1 = glioneuronal element= cystic components

2 = dysplasia3 = glial nodules

DNTDaumas-Duport C, Neurosurgery 1988;23:545

simple variant

complex variant

DNT

diffuse variant ?


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D E

3 yrs.

Ring-like enhancement in the periphery of the glioneuronal element, which may disappear on follow-up MRI


DNT WHO I 20.10.2015 stereotactic biopsies

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DNT WHO I 20.10.2015 stereotactic biopsies

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multifocal DNT

Heiland DH et al. Malignant Transformation of a Dysembryoplastic Neuroepithelial Tumor (DNET) Characterized by Genome-Wide Methylation Analysis. Journal of Neuropathology & Experimental Neurology Advance Access published February 27, 2016

DNT malignant2 cases in the literatureI don‘t believe it

16.10.182009 31.3.1520.5.1426.2.13

LEATs

• Long-term Epilepsy-associated tumors = tumor subtype associated with long-lasting epilepsy *

• GangliogliomaDNTpilocytic astrocytomaPXA

astrocytoma WHO °II, IIIoligodendroglioma WHO °II, III

isomorphic astrocytoma (Blümcke et al. 2004)

ANET (Wang et al. 2005, Lelloch-Tabiana et al. 2005)

Multinodular and Vacuolating Neuronal Tumor (Huse et al. 2013)

Papillary glioneuronal tumor (Kim and Suh 1997)

Glioneuronal tumor with neuropil islands (Teo et al. 1999)

* Luyken C, Blumcke I, Fimmers R, Urbach H, Elger CE, Wiestler OD, Schramm J. The spectrum of long-term epilepsy-associated tumors: long-term seizure and tumor outcome and neurosurgical aspects. Epilepsia 2003; 44: 822–830. Capper D et al. DNA methylation-based classification of central nervous system tumours. Nature 2018;

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pleomorphic xanthoastrocytoma (PXA)

• MRI: meningocerebral contrast enhancement and white matter edema on T2-weighted and FLAIRusually space-occupying effect.

may be impossible to distinguish PXA and ganglioglioma“composite PXA-GG lesions”

• Histopathology and Molecular testing: astrocytic tumor with superficial location in the cerebral hemispheres and involvement of the meninges

WHO grade II or III (anaplastic PXA = lesions with significant mitotic activity = > 5 mitoses per 10 high power fields).

• Five year overall survival rate around 70%, 10 years 60%.

• No IDH1/2 mutation. BRAF AV600E mutation in 66% of PXAs (Park et al. 2017).

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PXA WHO III, seit OP anfallsfrei

PXA pleomorphic xanthoastrocytoma WHO II

A B C

Pleomorphic xanthoastrocytoma WHO II° in a 14 year old boy with drug-resistant temporal lobe epilepsy. The meningo-cerebral contrast enhancement (C: arrow) is considered typical, but may also occur in gangliogliomas. An edgy imaging pattern and perifocal oedema are other common features (A, C: arrow)

PXA WHO III BRAF-V600EMutation

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pilocytic Astrocytoma (pA)

• well-circumscribed mass lesions with a cystic portion and a contrast-enhancing mural nodule.

• may be impossible to distinguish this tumor from a ganglioglioma, calcifications (present in 1/3 of gangliogliomas) favor the diagnosis ganglioglioma, larger tumors the diagnosis pilocytic astrocytoma

• In rare cases, a pilocytic astrocytoma spreads through the subarachnoid space, although histologically it may be still a WHO ° I tumor

• Histopathology and Molecular testing: biphasic pattern with varying proportion of compacted bipolar cells with Rosenthal fibers and loose textured multipolar cells with microcysts and granular bodies.

WHO ° I tumors, rarely anaplastic pilocytic astrocytomasBRAF V600E mutations in 15% of pilocytic astrocytomas (Park et al. 2017)

Note:enhancing cyst wall

pilocytic Astrocytoma (pA) WHO I

ANET

H&EEMA

ANET = angiocentric glioma

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ANET

• new 2007 WHO entity• angiocentric neuroepithelial tumor = angiocentric glioma

• n=18*: variably infiltrative tumor with histolog. features of astrocytoma and ependymoma

• MRI: cortical/ subcortical location, funnel-shaped extention towards the lateral ventricleT1: ribbon-like cortical hyperintensityT2: hyperintenseno contrast enhancement, no calcification

* Lellouch-Tubiana A et al. Angiocentric Neuroepithelial Tumor (ANET): A new Epilepsy-relatedclinicopathological entity with distinctive MRI. Brain Pathol 2005;15:281

* Wang M et al. Monomorphous angiocentric glioma: a distinctive epileptogenic neoplasm withfeatures of infiltrating astrocytoma and ependymoma. J Neuropathol Exp Neurol 2005;64:875

fibrillary astrocytoma WHO II

isomorphic astrocytoma WHO I

Schramm J, Luyken C, Urbach H, et al. Evidence for a clinically distinct new subtype of grade II astrocytomas in patients with long-term epilepsy. Neurosurgery. 2004;55:340–58.

isomorphic astrocytoma WHO I

• very homogenous appearance• relatively low T1-signal low cellularity

• Histopathology: Low cellularity, lack of mitotic activity, highly differentiated astroglial elements infiltrating into adjacent brain parenchyma

• WHO°I tumor

Schramm J, Luyken C, Urbach H, et al. Evidence for a clinically distinct new subtype of grade II astrocytomas in patients with long-term epilepsy. Neurosurgery. 2004;55:340–58.

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isomorphic astrocytoma Papillary Glioneuronal Tumor (PGNT)

• larger, partly cystic lesion with contrast enhancement. • multilobular involvement, periventricular, or intraventricular locations have been

described• maybe indistinguishable from a ganglioglioma or a PXA,

previously the PGNTwas considered a ganglioglioma subtype

• Histopathology and Molecular testing: Two components in varying proportions with papillary glial and intervening solid neuronal components

• WHO °I tumor with a lack of mitotic activity, Ki67 labeling index of 1–2% in the majority of cases. However, recurrent or fatal tumors have been described

• No 1p/19q loss, IDH1 or BRAF mutation, or epidermal growth factor (EGFR) amplification

Thom M, Blümcke I, Aronica E. Long-term epilepsy-associated tumors. Brain Pathol. 2012;22:350–79.

Papillary Glioneuronal Tumor (PGNT)

• first description 1998 Komori et al. Am J Surg Pathol 1998;22:1171

• WHO grade I• 4-75 years, ♂ = ♀• MRI: circumscripte, partly cystic lesion with variable contrast enhancement• DD: Ganglioglioma, pilocytic astrozytoma, (DNT)

Atri S et al. Papillary glioneuronal tumour: a report of a rare case and review of literature. Childs Nervous System 2007;23:349

PGNT

Hou Y et al. Papillary glioneuronal tumor (PGNT) exhibits a characteristic methylation profile and fusions involving PRKCA. Acta Neuropathologica 2019;137:837–846

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Multinodular and Vacuolating Neuronal Tumor of the Cerebrum (MVNT)

• Cluster of variably sized nodules in the deeper cortex layers and the gray white matter junction often interspersed by normal brain parenchyma

• can present with minimal or absent mass effect and no edema. Contrast enhancement is possible

• MRS: slight choline elevation

• Mesial temporal lobe is most common location

• Histopathology and molecular testing: Abnormal neuroepithelial elements in discrete and coalescent nodules, exhibiting conspicuous vacuolar alterations and being separated by apparently normal or astrogliotic neuroparenchyma. No BRAF V600E mutation

MVNTMultinodular and Vacuolating Neuronal Tumor of the Cerebrum

Nunes RH et al. Multinodular and vacuolating neuronal tumor of the cerebrum: a new “Leave Me Alone” lesion with a characteristic imaging pattern. AJNR Am J Neuroradiol. 2017;38:1899–904

MVNTMultinodular and Vacuolating Neuronal Tumor of the Cerebrum

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V.a. MVNT Multinodular and Vacuolating Neuronal Tumor of the Cerebrum

Summary

• LEAT = Ganglioglioma (65%), DNT (30%), PXA, pA, ANET, ... (5%)1

• The majority of LEAT has characteristic MRI features

1 Bien CG et al. Trends in presurgical evaluation …. from 1989-2009. JNNP 2013

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Documents

The past: LEAT-Study